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The fat storage system

Perhaps not a very sexy name but why name it something else than what it is?

After studying the functioning of our lipoproteins for a good 2 years (and still not finished learning!), it has finally become clear what those lipoprotein are meant for. As complex as it may be, the end goal is really simple:

  • To facilitate the storage of fat
  • To prepare for the storage of fat
  • To recuperate storage structure when it is no longer needed
  • Transfer fat storage from one location to another

Compare it with the complexity of a swiss watch. All that mind-boggling complexity of the internal components, in the end to simply show you the hour, minutes and seconds.

I want to show you how these lipids relate to the storage objective. Not only that, by understanding how it functions I also want to provide a perspective on how the system can be protective of atherosclerosis, indeed even reverse plaque formation (!)

A very bold claim to make indeed. Just consider it speculative from my side. I present you the info and you make up your own mind. It will never be substantial until research is done to elucidate this further.

What I’m going to present you now, although elaborate, is still a simplified picture. Elaborate enough to show how the system works and simplified enough to show the most important components.

The basics

This picture, for most people who have already looked into the lipids, will be fairly familiar.

  • Dietary fat gets stored in adipose tissue
  • 1st phase delivery is done by chylomicrons
  • 2nd phase delivery is done by the interplay of various lipoprotein (VLDL, IDL, LDL, HDL)

The role of liver-produced lipids and cholesterol

The fat needs to be pushed in a lipid droplet which resides inside the fat cell. So both the lipid droplet and the fat cell need to expand. They both have a membrane so the membrane needs to expand as well and that requires phospholipids and cholesterol.

Those phospholipids and cholesterol come from the liver-produced lipoprotein (VLDL, IDL, LDL). Keep those phospholipids in mind when you see growing or shrinking lipid storage because I won’t mention them any further.

Not important for the system although interesting, the type of fatty acids used to make up the phospholipids will determine how much stability is required and thus how much cholesterol will be absorbed in the membrane. This is why cholesterol values can vary depending on the type of fat you eat.

When we get into the fasted state, the fat cells will start to release the fat. Now the reverse happens. Both the lipid droplet and the fat cell will shrink so they need to reduce their membranes and thus also release the cholesterol that is in it.

This means the cell will have too much cholesterol and will get rid of it via HDL.

The fat goes out of the fat cells and will be used throughout the body. In the muscle cells specifically, the cells will store the lipids that may have been reduced from previous activity. So here the lipid droplets will grow and, you guessed it, also here the membrane of the droplet requires cholesterol.

At the bottom left you see the shrinking lipid content represented of the fat cells while on the bottom right you have the growing lipid content of the muscle cells.

As we proceed longer into the fasted state, the muscle reaches an equilibrium where the size of the lipid droplet is maintained at a roughly equal size. Keep in mind though, there is a high turnover in the lipid droplet. So there is a continuous breakdown and buildup of triglycerides but the end result is essentially zero change in size. There is no need for additional cholesterol or the removal of cholesterol.

Before the lipoprotein can support this delivery of membrane components, they must have the right composition. This change in composition is facilitated by cholesterol ester transfer protein (CETP). The liver produces CETP under stimulation of insulin so the level of insulin drives the level of CETP activity.

With CETP:

  • HDL-C exchanges cholesterol for triglycerides (TG) with VLDL, IDL and LDL (ApoB100 containing lipoprotein)
  • HDL is dedicated to remodeling ApoB100 lipoprotein
  • This means that VLDL, IDL and LDL lose their TG and in return gain cholesterol. They become cholesterol-enriched.  
  • This also means that HDL loses its cholesterol content and increases its TG content.
  • By being TG-rich, more HDL will be taken up by the liver creating lower circulating HDL particles in the blood
  • By being cholesterol-enriched, ApoB100 lipoprotein can be taken up by the cells

Without CETP:

  • HDL cannot offload its cholesterol to the ApoB100 lipoprotein and instead stays in circulation longer and accumulates more cholesterol
  • HDL is dedicated to cholesterol collection from cells
  • ApoE and LCAT drive HDL cholesterol accumulation so that it becomes big enough for uptake by the liver
  • The ApoB100 lipoprotein remain rich in TG and cannot be taken up by the cells

This is already becoming complex but you get a picture of how important CETP is. CETP will come back when we look at atherosclerosis..

Also note in the illustrations above, the free fatty acids aka non-esterified fatty acids (NEFA) (meaning not bound their usual glycerol backbone) are transported via albumin. This is an abundant available protein responsible for transporting the energy itself that will be used directly in the cells and also will be esterified (binding to glycerol) as triglycerides and stored in the lipid droplets inside the cells.

Getting everything across the cell membrane

There are 2 important factors to absorb the fatty acids and membrane structures. Note again, we focus primarily on cholesterol although the phospholipids are part of it.

These are not just gates that are open 100%, accepting anything at all times. How are they regulated? How do we get the NEFA and cholesterol across?

LPL

  • ApoC-II reduces on a high fat diet. This means that more NEFA is imported via albumin
  • Sterol regulatory element-binding protein 1 (SREBP1) is activated under lower cellular cholesterol content and reduces LPL expression
    • => This is a negative feedback which reduces NEFA import. When there is a shortage of cholesterol to build storage then you need to lower NEFA to avoid accumulation in the cell
  • The fat cell LPL is activated by insulin.  Muscle cell LPL is activated by low insulin
    • => Insulin prioritizes fat storage in fat cells. => When insulin lowers, the energy is distributed and taken up by the other cells
  • LPL is increased during and after exercise. During those moments, there is an increased demand for energy

LDLr

  • Requires cholesterol-rich lipoprotein (VLDL, IDL, LDL)
  • Endocytosis of the lipoprotein (complete uptake of the lipoprotein)
  • Support expansion of the lipid droplet membrane via cholesterol import
  • Insulin activates SREBP1 and SREBP1 activates LDLr. As expected because SREBP1 shows there is a need for cholesterol and when driven by insulin it means we are focusing on storing fat.

LDLr in the muscle

  • exercise, fasting activates SREBP1 via MAPK. Similar to insulin, we also want to store fat simply to respond to a higher fat metabolism need. When fat metabolism increases, there is need for a bigger local buffer, a bigger lipid droplet.

In summary so far, we can say that a diet existing out of high fat quantities in combination with a high fat metabolism causes a continuous growing and shrinking of the fat cells. If that is combined with exercise then also the muscles are faced with this growing and shrinking. The timeframe and the volume of fat handled causes those cells and lipid droplets to grow to larger sizes and to shrink to smaller sizes, compared to a diet and lifestyle where glucose is a major energy source. This leads to a lower flux of the fat storage.

Such an intensified remodeling on high fat/high activity requires more support from the circulating lipoprotein!

This has to be supported by the lipoproteins that we are familiar with. VLDL, LDL and HDL. Moreover, in order to be able to receive the next bolus of incoming fat it is good to have the right types and level of lipoprotein ready to support this.

What is the best way to accommodate a high fat meal so that we can swiftly provide the necessary membrane components for expansion?

  • TG-rich (large buoyant) LDL
  • High cholesterol levels on HDL

When the meal comes in, insulin comes up and will stimulate CETP. With those 2 listed above, CETP can immediately remodel LDL to become enriched with cholesterol so that it can be taken up by the fat cells. Both lipoproteins need to be sufficiently high to support a faster clearance of the fat into storage.

It’s my engineer thinking but would it be just a coincidence that LDL goes up under such high fat intake and consumption? This high flux signals the need for a greater storage capacity so doesn’t it make sense to have more of the membrane components ready to maximize the storage capacity? Could that be the reason why fasting LDL particles and HDL cholesterol are high? As soon as CETP kicks into action you’ll now have a lot of LDL particles ready to accept cholesterol and support the membrane expansion of fat cells and their lipid droplets.

You NEED high LDL and HDL when you have a high dietary fat intake

High fasting LDL, HDL and low TG for lean individuals on a ketogenic diet

With the above information you understand the need for it. But how do we arrive at that situation? The following are general mechanisms that apply to everybody but the extend to which they get applied is determined by many factors such as the amount of fat you eat, exercise level, your level of insulin etc… There are other factors but insulin is a very big player in all of this.

  • Under fasted conditions, insulin is sufficiently low to keep cholesterol production very low. When fasted we are not interested in storing fat. The liver preserves most fatty acids for ketogenesis, bile production and its own fat metabolism. Both fatty acids and cholesterol production is low in such a way that it has shifted from VLDL production towards large buoyant LDL
  • Large buoyant LDL stays in circulation longer because it is cholesterol poor, ApoE rich and thus has a lower ability to be taken up by LDLr for endocytosis. That ApoE enrichment is also the reason why small dense LDL (sdLDL) has a lower affinity for LDLr
  • Low insulin keeps CETP low, thus VLDL and LDL cannot acquire sufficient cholesterol from HDL for endocytosis by LDLr
  • Due to low CETP, the cholesterol load on HDL increases and minimizes exchange with VLDL, IDL, LDL.
  • With very low to no production of VLDL sized lipoprotein, there are almost no lipoproteins that can acquire ApoC-II for lipolysis by LPL thus almost all skeletal muscle NEFA are derived from albumin

So on the production side we have lower production but more of the lipoprotein in the LDL size, in circulation there is no remodeling taking place and due to this the uptake by the skeletal muscle is much lower.

When the skeletal muscles are full and reduce their uptake of fatty acids, this will lead to a higher return of those fatty acids towards the liver. So the release of fatty acids from the fat cells is temporarily higher than the uptake by the other cells. This accumulation leads to a larger availability of fatty acids in the liver so that it can augment its production of TG-rich LDL.

Now it will depend on how big this discrepancy is. This higher level of fatty acids in the liver also causes more ketones (BHB) to be produced. The body may respond to this by slightly increasing insulin. This will cap BHB production, reduce the rate of fatty acid release from fat cells and slightly increase cholesterol production allowing the liver to temporarily produce more VLDL-sized lipoprotein. It will also slightly elevate CETP so that storage can be facilitated to get rid of the excess fat in circulation.

You may notice this as a slight elevation in your fasted triglycerides. It is only temporarily as it is part of an exercise to balance out demand and supply.

Buffering for energy usage

and issues with it

Still following so far? OK. Now lets have a look at issues with storage.

Just like with glucose, the fat is stored in large quantity in a central place and from there distributed to local storage in the muscle. Central is put in quotes, mainly referring to the adipocytes. It is supposed to sit under our skin and well.. our skin is completely wrapped around our body so it is a bit strange to say central.

I’ve illustrated glycogen here just for comparison. Just note that I’m continuing only talking about the fat.

Storage limitation -> muscle insulin resistance

At some point, all of these buffers have to signal when they are full and (temporarily) cannot take in any more fat. This signaling is provided by 1,2DAG. An intermediate fatty acid that is formed when synthesizing triglycerides for storage.

  • TG synthesis generates 1,2DAG
  • Accumulation leads to translocation of 1,2DAG into the cell membrane
  • 1,2DAG attracts Protein Kinase C (PKC) to the membrane
  • PKC internalizes LDLr -> No uptake of cholesterol-rich lipoprotein
  • PKC inhibits Insulin Receptor Signaling (IRS) -> insulin resistance!
  • 1,2DAG is preferentially hydrolyzed (broken down) for fat metabolism
  • Exercise, fasting, high fat diets increase fat metabolism
    • Increased clearance of 1,2DAG via DGAT1 expression (exercise)
    • Restores insulin sensitivity
    • Increases SREBP1 expression -> increases LDLr expression -> increases lipid storage capacity

It does create a conflict though because the accumulation also indicates the need for more cholesterol but 1,2DAG prevents this by blocking LDLr. You cannot signal stop and store more at the same time so how do we end up in this situation?

  • Increased storage in lipid droplet reduces cellular cholesterol
  • lower cellular cholesterol -> SREBP1 activation -> increase LDLr expression
  • 1,2DAG accumulation threshold blocks LDLr via PKC
    • Prioritize cellular cholesterol production instead of via extracellular uptake
    • Reduce cellular fatty acid accumulation

In and of itself this is a normal mechanism. By not taking up both lipids and membrane components, other cells can manage to top up their reserves so you get an even distribution. The problem however is when every cell is topped up and you still have too much in circulation.

It will lead to higher insulin levels because too much energy in circulation drives up insulin to try and store that excess. That will lead to more VLDL-bound TG, higher CETP thus higher cholesterol bound to LDL (higher cholesterol/particle ratio) and lower HDL.

But with cells that have enough fat accumulated, they say no to insulin so insulin does what it is supposed to do, form the lipoprotein particles that are required for storage but all the cells keep their doors closed.

Exactly the pathologic lipid profile that we know and should fear.

  • Increased VLDL triglycerides
  • Increased cholesterol-rich LDL
  • Decreased HDL (lower cholesterol/particle ratio)

Why should we fear it? Because it has a good proxy value towards atherosclerosis.

Atherosclerosis

saved by enhanced fat metabolism?

As mentioned in the introduction, it may actually mean reversal of plaque! The very low insulin obtained through being lean, very low carbohydrate diet with high fat intake creates cholesterol-enriched – ApoE-enriched HDL which drives up their LCAT activity. LCAT stimulates cholesterol release from macrophages.

Macrophages in atherosclerosis aren’t only gobbling up cholesterol, they also accumulate triglycerides. It turns out though that cholesterol efflux helps to switch gears into fat metabolism so the macrophage can reduce its fat storage. If you cannot store the fat, you have to start using it for energy.

This whole deep dive into research led me to the following, to my view important, observation. These M1 macrophages actually maintain import and storage of fatty acids (through LDLr). Only by ‘forcing’ cholesterol efflux are we able to reverse the situation, pushing them to metabolize the fat. PPARy is known to do this and PPARy is activated by BHB, thus a ketogenic diet. PPARy is also activated under low cellular cholesterol, via SREBP1. This has been evidenced in liver and fat cells but likely also applies to macrophages. And a deactivation of PPARy was accomplished by re-addition of cholesterol.

PPARy expression hence seems subject to a tight and fast control by alterations in intracellular cholesterol levels, and this effect is mediated by the SREBP family of transcription factors.

source: https://pubmed.ncbi.nlm.nih.gov/10409739/ “Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism”

A paper showed me that macrophages are able to restore insulin resistance in skeletal muscle of diabetics. Insulin resistance that is caused by 1,2DAG as we have seen. So if macrophages carry the capacity to somehow neutralize 1,2DAG from the membrane then maybe they apply this capacity also to their own membrane.

This is still an area I need to find research on but we already see that macrophages do not exhibit a stop mechanism like other cells.

That would explain why they get so big with fat and cholesterol. The only way out of this situation is to enhance the efflux of cholesterol from the macrophages. And the only way to do that is by creating big cholesterol-rich HDL so that it can acquire ApoE and drive up LCAT. And the only way to do that is by getting your insulin very low. And the only way to do that sustainably(!) is by adopting a very low carb diet and getting lean.

Get those cells to push out cholesterol like it’s nobodies business!

update 2021/09/21: A paper came out showing how BHB could be reversing vascular calcification through autophagy. Although it is separate from the described mechanism above, it does pertain to enhancing fat metabolism as a way to reverse the diseased state.

“β-Hydroxybutyric Inhibits Vascular Calcification via Autophagy Enhancement in Models Induced by High Phosphate.” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8422966/

—– T H E – E N D —–

Sources

My previous writings on this topic with references that over time have contributed to my understanding.

Further resources, specifically for this article

LXR

https://pubmed.ncbi.nlm.nih.gov/12697904/ “Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433546/ “Liver X receptors in lipid signaling and membrane homeostasis”

Cholesterol efflux

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159082/ “Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport”

https://pubmed.ncbi.nlm.nih.gov/17390217/ “Stimulation of lipolysis enhances the rate of cholesterol efflux to HDL in adipocytes”

Lipids on a ketogenic diet

https://academic.oup.com/jn/article/135/6/1339/4663837 “Modification of Lipoproteins by Very Low-Carbohydrate Diets”

LPL receptor

https://www.ncbi.nlm.nih.gov/books/NBK537040/ “Biochemistry, Lipoprotein Lipase”

https://www.sciencedirect.com/science/article/pii/S0022227520380901 “Effects of dietary carbohydrate and fat on plasma lipoproteins and apolipoproteins C-II and C-III in healthy men”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705268/ “Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism”

https://www.ahajournals.org/doi/full/10.1161/01.ATV.19.3.472 “Role of ApoCs in Lipoprotein Metabolism”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705268/ “Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism”

https://pubmed.ncbi.nlm.nih.gov/11090277/ “Induction of LPL gene expression by sterols is mediated by a sterol regulatory element and is independent of the presence of multiple E boxes”

LDL in skeletal muscle

https://pubmed.ncbi.nlm.nih.gov/9696990/ “Skeletal muscle lipoprotein lipase: molecular regulation and physiological effects in relation to exercise”

https://www.sciencedirect.com/science/article/pii/S0925443902001692 “Expression and regulation by insulin of low-density lipoprotein receptor-related protein mRNA in human skeletal muscle”

https://diabetes.diabetesjournals.org/content/50/11/2585 “In Muscle-Specific Lipoprotein Lipase−Overexpressing Mice, Muscle Triglyceride Content Is Increased Without Inhibition of Insulin-Stimulated Whole-Body and Muscle-Specific Glucose Uptake”

https://pubmed.ncbi.nlm.nih.gov/17046550/ “Fasting decreases free fatty acid turnover in mice overexpressing skeletal muscle lipoprotein lipase”

in liver

https://pubmed.ncbi.nlm.nih.gov/12951168/ “Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity”

LDL receptor

https://www.ahajournals.org/doi/10.1161/circresaha.114.301621 “PCSK9 – A key modulator of cardiovascular health”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071588/ “Activation of LDL Receptor (LDLR) Expression by Small RNAs Complementary to a Noncoding Transcript that Overlaps the LDLR Promoter”

https://pubmed.ncbi.nlm.nih.gov/16449296/ “Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle”

https://diabetes.diabetesjournals.org/content/69/5/848 “Exercise and Muscle Lipid Content, Composition, and Localization: Influence on Muscle Insulin Sensitivity”

https://pubmed.ncbi.nlm.nih.gov/9010277/ “Low density lipoprotein receptor expression and function in human polymorphonuclear leucocytes”

https://pubmed.ncbi.nlm.nih.gov/3237238/ “The binding of lipoproteins to human muscle cells: binding and uptake of LDL, HDL, and alpha-tocopherol”

https://journals.physiology.org/doi/full/10.1152/ajpendo.00543.2005 “Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle”

https://www.cell.com/fulltext/S0092-8674(00)80213-5 “The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor”

https://www.ahajournals.org/doi/full/10.1161/01.ATV.18.3.466 “Influence of ApoE Content on Receptor Binding of Large, Buoyant LDL in Subjects With Different LDL Subclass Phenotypes”

https://pubmed.ncbi.nlm.nih.gov/8254047/ -> https://dm5migu4zj3pb.cloudfront.net/manuscripts/116000/116915/cache/116915.1-20201218131521-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf “Accumulation of “small dense” low density lipoproteins (LDL) in a homozygous patients with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor”

https://pubmed.ncbi.nlm.nih.gov/16670767/ “Putting cholesterol in its place: apoE and reverse cholesterol transport”

Lipids

https://www.sciencedirect.com/science/article/pii/S0022227520380901 “Effects of dietary carbohydrate and fat on plasma lipoproteins and apolipoproteins C-II and C-III in healthy men”

https://www.britannica.com/science/lipid/Classification-and-formation “Classification and formation”

Macrophages

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767414/ “Lipid Droplets And Cellular Lipid Metabolism”

https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0056601 “Skeletal Muscle Insulin Resistance Associated with Cholesterol-Induced Activation of Macrophages Is Prevented by High Density Lipoprotein”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868788/ “Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957345/ “High-Density Lipoprotein Maintains Skeletal Muscle Function by Modulating Cellular Respiration in Mice”

https://pubmed.ncbi.nlm.nih.gov/29217413/ “Apolipoprotein E-containing high-density lipoprotein (HDL) modifies the impact of cholesterol-overloaded HDL on incident coronary heart disease risk: A community-based cohort study”

https://pubmed.ncbi.nlm.nih.gov/16670775/ “HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway”

https://www.nature.com/articles/aps201093 “A novel model of cholesterol efflux from lipid-loaded cells”

https://www.cell.com/cell-metabolism/references/S1550-4131(07)00166-0 “PPARγ Activation Primes Human Monocytes into Alternative M2 Macrophages with Anti-inflammatory Properties”

https://pubmed.ncbi.nlm.nih.gov/22207731/ “Regulation of lipid droplet cholesterol efflux from macrophage foam cells”

https://www.nature.com/articles/s41598-018-34305-x “A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition”

Lipid droplet

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575688/ “DAG tales: the multiple faces of diacylglycerol—stereochemistry, metabolism, and signaling”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526153/ “The Biophysics and Cell Biology of Lipid Droplets”

Muscle cell

https://www.sciencedirect.com/science/article/pii/S0005273615003867 “Alteration of lipid membrane structure and dynamics by diacylglycerols with unsaturated chains”

https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0056601 “Skeletal Muscle Insulin Resistance Associated with Cholesterol-Induced Activation of Macrophages Is Prevented by High Density Lipoprotein”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665384/ “High triacylglycerol turnover rate in human skeletal muscle”

https://journals.physiology.org/doi/full/10.1152/ajpendo.00543.2005 “Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1866250/ “Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510842/ “Studies on the Substrate and Stereo/Regioselectivity of Adipose Triglyceride Lipase, Hormone-sensitive Lipase, and Diacylglycerol-O-acyltransferases”

Dawn phenomenon

https://joe.bioscientifica.com/view/journals/joe/231/3/235.xml “Melatonin modifies basal and stimulated insulin secretion via NADPH oxidase”

https://pubmed.ncbi.nlm.nih.gov/6368151/  “Fasting early morning rise in peripheral insulin: evidence of the dawn phenomenon in nondiabetes”

PPARy

https://pubmed.ncbi.nlm.nih.gov/10409739/ “Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1: implications for adipocyte differentiation and metabolism”

Rebuttal of the Lipid Energy Model hypothesis

On the 20th of May 2022, the Lipid Energy Model (LEM) was published in an attempt to explain the drastic elevation seen in LDL-c amongst lean individuals who are on a high fat diet with low carbohydrates.

The purpose of this rebuttal is to open up discussion on some aspects of the hypothesis so that understanding advances in order to validate or improve the model to reflect an accurate description of why these individuals see their LDL-c rise so drastically.

Certain effects are described which I will address with information that will highlight aspects opposing the claims made.

But first a quote from the publication summarizing the model.

  •  Reduction in dietary carbohydrates and depletion of hepatic glycogen stores results in a greater demand for fat as a metabolic fuel, to compensate for reduced glucose availability.
  •  Decreased insulin, leptin, and other changes to the hormonal milieu, result in increased hormone-sensitive lipase (HSL)-mediated lipolysis in adipocytes and greater secretion of non-esterified fatty acids (NEFAs) into the bloodstream.
  •  In addition to heightened use by tissues in the periphery, there is a greater rate of uptake of NEFAs by the liver. Under these conditions, there is a greater rate of synthesis of TGs from the increased fatty acid pool within hepatocytes.
  •  Increased rates of TG synthesis in the liver leads to increased rates of hepatic assembly and secretion of TG-rich VLDL.
  •  The increased VLDL secretion rates, in concert with greater LPL-mediated turnover of VLDL in peripheral tissues, and greater transfer of VLDL surface components (including free cholesterol) to HDL, result in higher plasma levels of LDL-C and HDL-C.

The highlighted parts will be the focus of this rebuttal.

Increased synthesis of triglycerides resulting in higher hepatic secretion rate of VLDL

The model describes a higher release of non-esterified fatty acids (NEFA) from adiposity. This is true as research shows us a higher circulation of those fatty acids thus it is possible that the liver receives more of these NEFA.

An argument in favor of the LEM is that indeed a higher perfusion of the liver with NEFA can lead to a higher re-esterification meaning the synthesis of triglycerides based upon these NEFA (https://www.pnas.org/doi/10.1073/pnas.1423952112).

A second argument is that insulin prevents the secretion of the ApoB lipoprotein (https://www.sciencedirect.com/science/article/abs/pii/S0006291X11002117?via%3Dihub) thus under conditions of low insulin such as a high fat low carb diet, you could reason that secretion is actually increased.

1. Glucagon

However, such studies focus on the role of insulin. Glucagon, when insulin is low, rises significantly. In a paper from Volek et all. comparing ultra-endurance athletes on high carb versus a ketogenic diet (https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.31.1_supplement.1036.3) at baseline we see a glucagon level which is >50% higher.

Glucagon is important because the liver increases beta-oxidation in response to glucagon in favor of re-esterification (https://onlinelibrary.wiley.com/doi/10.1111/jdi.13315 ; https://www.frontiersin.org/articles/10.3389/fphys.2019.00413/full). The latter study also alludes to a possible glucagon-secretion stimulation by fatty acids but results are mixed and need further study.

By inhibiting the formation of malonyl-CoA, glucagon diverts FFAs to beta-oxidation rather than re-esterification into TGs (Figure 2).

In vitro results show that glucagon diverts re-esterification of fatty acids away in favor of ketone body production (https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.1840130620)

The stimulation of AMPK by glucagon is also noted elsewhere (https://diabetesjournals.org/diabetes/article/69/Supplement_1/220-LB/56113/220-LB-Glucagon-Promotes-Hepatic-Autophagy-by-AMPK). In the chain of events, AMPK will inhibit HMG-CoA reductase which results in a reduction in cholesterol synthesis (https://physoc.onlinelibrary.wiley.com/doi/10.1113/jphysiol.2006.108506). More information on HMG-CoA reductase and cholesterol follows further down. AMPK, via GPAT, also reduces the re-esterification of fatty acids.

A ketogenic diet has the potential to increase hepatic AMPK (https://www.sciencedirect.com/science/article/abs/pii/S0955286321000401 ; https://journals.physiology.org/doi/full/10.1152/ajpendo.00717.2006). When AMPK is elevated, it will reduce hepatic triglyceride content and stimulate fatty acid oxidation as we’ve just seen before (https://www.mdpi.com/1422-0067/19/9/2826/htm)

2. Higher secretion rate

A simple argument against a higher secretion rate of triglyceride-rich VLDLs is that this should be reflected in the blood. Yet part of the characteristics is that these individuals have low triglycerides.

When a blood sample is taken, it reflects what is available at that point in the artery. If low levels are measured then that artery can only deliver a low quantity of triglycerides. Sampling blood from different arteries in the blood should clarify if there is perhaps an unequal distribution to the arm or perhaps a greater or faster lipoprotein lipase activity takes place. This does go against the purpose explained in the model. Energy delivery must be possible to all parts of the body thus it should be detected in higher VLDL particle availability in blood samples if this is part of the increased distribution network.

3. VLDL assembly

As stated earlier, low insulin is a condition for increased ApoB secretion. For the liver to create and secrete a VLDL particle, it is not only depending on low insulin but also triglyceride availability and other components.

Triglycerides, if not available in sufficient quantity will result in degraded ApoB (https://www.jlr.org/article/S0022-2275(20)30605-2/fulltext). On the opposite side, high continuous availability of fatty acids may also result in reduced ApoB production although it initially stimulates higher secretion. This raises the question if the condition in our subjects falls under the chronic high availability. Yet we also have glucagon interfering with triglyceride formation.

Glycerol is required to attach 3 fatty acids to form triglyceride. The following paper (https://www.sciencedirect.com/science/article/pii/S0021915013001767) hints at glycerol availability as a factor that determines VLDL secretion. We need to be careful with interpretation as this one is done under lactate infusion. It should be kept in mind that with increased glucagon, glycerol is used as a substrate for gluconeogenesis and thus may be available in limited amounts.

In 60h-fasted subjects, they concluded that most glycerol is not taken up by the liver (https://journals.physiology.org/doi/abs/10.1152/ajpendo.1996.271.6.E1110)

Thus, in 60 h-fasted individuals, most glycerol uptake does not occur in liver, and the extent of fatty acid reesterification in liver is in doubt.

Cholesterol synthesis in the liver is in part dependent on the liver X receptor (LXR) (https://www.sciencedirect.com/science/article/pii/S0021925819362167). LXR is stimulated by insulin so we can expect that in our subjects with low insulin, there will also be a low hepatic synthesis of cholesterol.

furthermore, cholesterol synthesis depends on the HMG-Coa reductase enzyme to send HMG-Coa down that pathway. Insulin increases the mRNA and protein production while glucagon and fasting lower both. (https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(19)62026-0).

4. Counter observations

When looking at VLDL secretion rates via labeled omega-3 fatty acids in pill form in obese subjects, they noted a reduction (https://academic.oup.com/ajcn/article/77/2/300/4689666). According to the LEM one would expect a higher secretion given that they were having an additional dietary fatty acid supply. Of course the effect could be different as these subjects were obese and not on a high fat low carb diet which would result in different hormonal signaling. Yet it would be interesting to have an explanation for the observation as more fatty acids reached the liver.

5. Thyroid

Under low dietary carbohydrate conditions, T3 levels tend to drop with an increase in reverse T3. Even when there is no reduction in caloric value (https://pubmed.ncbi.nlm.nih.gov/6761185/).

T3 is a regulator of metabolism, it also helps in the transcription and stabilization of the HMG-Coa reductase mRNA (https://pubmed.ncbi.nlm.nih.gov/10782041/)

To further emphasize on the importance of free T3, VLDL-TG production has been investigated and found correlated independently with fasting insulin levels and resting energy expenditure (https://www.jlr.org/article/S0022-2275(20)43420-0/fulltext) and unrelated to free fatty acid availability or body fat distribution.

6. LDL clearance

As a consequence of higher VLDL secretion rates, combined with reduction in size through lipase activity, this could indeed lead to an increase in LDL particles. However, one cannot expect a higher level of secretion without a concomitant increase in clearance or LDL particle levels would continue to rise indefinitely. The LEM does not make any comments on such balancing so it is by definition incomplete.

Because the state of elevated LDL-c in our individuals is associated with insulin, we must note that the hepatic LDL receptor is reduced under insulin stimulation via stimulation of PCSK9 (https://www.atherosclerosis-journal.com/article/S0021-9150(08)00556-X/fulltext).

This is in line with evidence that point to glucagon for degrading PCSK9 which allows LDL receptor expression (https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313648).

However, those are not the only determinants of LDL receptor expression. Under fasting conditions, a reduction in LDL receptor is observed, at least in part due to lower free T3, which is abolished when free T3 levels are maintained at levels equal to non-fasting (https://www.sciencedirect.com/science/article/abs/pii/S1357272597001209). The authors conclude that the increase in LDL-c results from the reduction of LDL receptors.

One other modulator of LDL receptor expression is the type of fat. The more saturated the fatty acids are, the more LDL receptor is reduced and vice versa (https://www.jlr.org/article/S0022-2275(20)37254-0/pdf).

Other studies have shown that there is a shift in the low density lipoprotein particles towards larger version of it called pattern A (https://academic.oup.com/jn/article/135/6/1339/4663837). As these LDL particles grow in size, they reduce their affinity to bind to the LDL receptor with a reduction in clearance as a result (https://www.atherosclerosis-journal.com/article/S0021-9150(01)00565-2/fulltext ; https://pubs.acs.org/doi/10.1021/bi048825z).

7. Albumin

In order for high amounts of NEFA to reach the liver, we have to look at how NEFA reach the liver. The protein albumin has a large carrying capacity for NEFA up to the point that it is responsible for carrying most of it and depending on its concentration even reduces LDL capacity for uptake (https://pdf.sciencedirectassets.com/778418/1-s2.0-S0022227520X64315/1-s2.0-S0022227520394736/main.pdf).

Albumin is the largest carrier of NEFA in the blood stream covering 99%. It needs to be reviewed if this is still valid for our subjects on a high fat low carb diet (https://www.mdpi.com/1422-0067/22/16/8411/htm).

Albumin is the carrier of 99% of non-esterified fatty acid (FA) present in blood plasma. Classically, albumin is shown to have 7 high- and more than 20 low-affinity FA-binding sites [6,58]

The length and saturation level of fatty acids is important in the distribution of the carriers albumin and lipoprotein. Long chain saturated fatty acids are competed for but other fatty acids are predominantly bound to albumin (https://pdf.sciencedirectassets.com/778418/1-s2.0-S0022227520X62717/1-s2.0-S0022227520367237/main.pdf ; https://www.sciencedirect.com/science/article/abs/pii/0005276065901293)

Greater transfer of VLDL surface components (including free cholesterol) to HDL

This is important because in order for VLDL to turn into LDL, it needs to reduce its lipid content and therefor also structural components such as cholesterol to reshape the particle. This restructuring takes place in the plasma.

1. CETP

Such restructuring is carried out by CETP leading to the exchange where HDL donates cholesterol to ApoB containing particles (VLDL, IDL, LDL) and receives fatty acids. Under low insulin conditions, CETP activity reduces.

As alluded to earlier, on a ketogenic diet there is a shift in LDL particle size from pattern B towards pattern A.

Austin et al in a classic paper70 found that pattern B was associated with a two-fold increase in plasma triglyceride, higher plasma apoB and IDL levels and reduced HDL cholesterol and apoA-I concentration, ie, small, dense LDL did not appear in isolation from other plasma lipid abnormalities.

https://www.ahajournals.org/doi/10.1161/01.ATV.17.12.3542

When CETP activity is high, it leads to smaller LDL particles, is associated with metabolic syndrome, reduces HDL-c, increases small dense LDL (https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2362.1994.tb00987.x ; https://cardiab.biomedcentral.com/articles/10.1186/s12933-016-0428-z ; https://www.sciencedirect.com/science/article/pii/S0022227520328005)

We have already seen the involvement of LXR in cholesterol synthesis but it is also responsible for CETP regulation (https://www.atherosclerosis-journal.com/article/S0021-9150(10)00316-3/fulltext). AMPK directly inhibits LXR (https://www.ijbs.com/v07p0645.htm) while it requires insulin to be stimulated.

Under low CETP activity, HDL has greater cholesterol accumulation while LDL remains loaded with its triglyceride content. This is a favorable situation as this allows HDL to become large enough to incorporate ApoE. That in turn will allow the particle to increase LCAT activity which drives the export of cholesterol from cells (such as macrophages).

Discussion

It is clear that a low fasting insulin and high glucagon allows for a higher VLDL secretion rate and there are studies to show this but those studies are done on subjects of which we can expect to have some hepatic fat accumulated before the trial.

NAFLD is cleared in a couple of months abstaining from carbohydrates showing a high clearance rate. Our subjects who are marked with very high levels of LDL-c however have clear livers so that the high secretion rate cannot be sustained while at the same time, an elevated fasting glucagon diverts away from re-esterification.

With the evidence presented, there are 3 main points to consider.

First, a state in which insulin is low and glucagon is high tells the body to increase its efficiency. A system in which the liver takes up fatty acids to produce ketones, use fatty acids for its own energy provision and also uses fatty acids to produce triglycerides and cholesterol and produce ApoB protein in order to build VLDL particles and distribute fatty acids for energy could benefit from having those fatty acids delivered directly from adipose to all cells in need of that energy. This allows the liver to focus on its own energy provision and production of ketones. Fatty acids can be delivered directly via albumin which has a big capacity to carry NEFA but also by keeping LDL-sized ApoB particles in circulation longer so that they can carry out the NEFA transactions.

The amino acids required for ApoB production also need to be saved in this state as the continued production and degradation requires ATP. The VLDL assembly requires energy while, if hepatic AMPK is indeed elevated, there is a need to be conservative with energy.

Low VLDL output would be a problem if cells have a requirement to receive the NEFA from adipose but we have seen that albumin is able to carry out this task.

Second, the concept of increased production does not hold unless there is also an increase in clearance. The LEM does not make note of any such increase. It does make note of an increase in lipoprotein lipase which essentially means that the lipoprotein particle is stripped of its triglyceride content but does not remove the ApoB protein from circulation. This clearance from circulation is done by the liver LDL receptor but, in contrast to requiring higher clearance, this LDL receptor is reduced under low free T3.

Third, the premise of high VLDL secretion and lipolysis in combination with remodeling assisted by HDL, to my view, needs to be corrected towards a reduced hepatic secretion of ApoB particles in a lower size range (likely LDL) with a reduction in remodeling due to low CETP activity, combined with a longer median residence of LDL particles in circulation.

Finally, I hope that with this article there is sufficient content to reconsider the statements around increased hepatic VLDL secretion. I do encourage researchers to follow the recommendation of the LEM authors to investigate on the true reason why LDLc increases so dramatically in these individuals.

As I have boldly stated based on my own summary of the main purpose of the lipid system, the potential implications can be quite high with the potential to reverse atherosclerosis should my analysis prove to be correct.

Strength and weaknesses

Some of the studies referenced provide results obtained from animals. These are good for mechanistical results although still require validation in humans. However for example enzymatic activity in the liver would require obtaining liver samples which require invasive procedures on living humans. Such studies will not be approved.

Because the increase seen in LDL-c is framed under narrow conditions, almost none of the research is done under such conditions so one has to be careful if the results do translate correctly.

Protein content in the diet can be a differentiator as it too has an effect on the main hormones glucagon and insulin which are responsible for most of the effects. In addition protein may influence the thyroid as well.

What is not addressed, and to which dietary protein partakes, is the effects across the day with several meals. In general, a meal will stimulate insulin to some degree. A high fat meal together with sufficient insulin stimulation will accumulate lipids in the postprandial phase allowing for a temporary increased production of VLDLs until insulin has subsided to its fasting levels and the liver has cleared its accumulated fatty acids.

However, sufficient resources cover the mechanisms by which we can expect an increase or decrease in VLDL secretion. We can reasonably expect that, in these individuals, there is a low fasting level of insulin and increased fasting level of glucagon in conjunction with a decrease in active T3 and low CETP activity.

Investigating these parameters in this sub-population could help identify if these aspects are truly relevant towards the noted increase in LDL-c.

– – – T H E – E N D – – –

A world dominated by psychopaths

Our gut feeling says this is not the most ideal vision.  Yet, with what I am about to unravel, this is exactly the path we are on.  This article will be big and lengthy because I want you to grasp the full extent of the reach, the ideas and the consequences.  This is about your future and you cannot buy into it on a 2-line summary.  I promise to be as concise as possible.

Let me start by first introducing the foundation.

Globalists

The history of the Rockefeller Foundation (RF) is one that started by its philanthropic founder.  Rockefeller was the first to own $1 billion dollars, at the time that was 2% of the US GDP.  He made it a point to give away 10% of his fortune to charity.  A close friend of his stepped in and changed this with the intent on improving evidence-based medicine.  All the medical schools (Harvard medical school, Yale medical school and many others)  and pharmaceuticals (Pfizer, Moderna) started to receive donations and investments.

Probably through his graduation at Harvard, Klaus Schwab got into contact with the RF.  This led to the development of an ideology of how the world best operates.  They weren’t just dreaming though.  They had the financial backing of the RF and took action to put their ideas into place.

Klaus Schwab established the World Economic Forum (WEF), which is known from the gatherings in Davos where country leaders, politicians and multinational corporations join to connect with each other and listen to the agenda that is set by Klaus Schwab.

What is this ideology?

By 2010 they were already well developed influential organizations and decided to each publish a review of the world showing where it is heading towards and how to prepare for it.  Those in charge of policy should prepare with legislation, those in charge of companies should prepare through business opportunities, a first mover advantage.

The publication “Scenarios for the Future of Technology and International Development” from the RF presents 4 potential future scenarios (http://www.nommeraadio.ee/meedia/pdf/RRS/Rockefeller%20Foundation.pdf

The WEF review “Everybody’s Business: Strengthening International Cooperation in a More Interdependent World” is a more extensive 604 page counting analysis of the world problems today (2010) and how to solve these issues.  (https://www3.weforum.org/docs/WEF_GRI_EverybodysBusiness_Report_2010.pdf)

More recently, Klaus Schwab also published a book called “The Great Reset”, written in 2020, which further details the vision. http://reparti.free.fr/schwab2020.pdf 

It is the view of a world in which there is a global governance run by the elites of society, a global public-private partnership.  Trade is open and free across the globe.  Scientific information is open and freely accessible to everybody, stimulating innovation and technology.  They aim to have a healthy population, food available to everybody.  Global Warming must be resolved.  In other words, a peaceful and prosperous globe for everybody.

Particularly technology is seen as a key element to greatly advance our civilization.

The following image depicts how they see this organized.

To exemplify, we see here on twitter Tedros Adhanom Ghebreyesus meeting with Klaus Schwab discussing and shaping the future.  You cannot have the above organization without meeting each other and align on such a project.

Director-General of the WHO https://en.wikipedia.org/wiki/Tedros_Adhanom_Ghebreyesus 

So far you may think it sounds good, an ideal world to live in so nothing wrong with that.  Sit back and relax, right?  Can we really expect these people to have the population’s wellbeing as their highest value?  Perhaps it sounds too good to be true?

Let’s review the RF document a bit more in detail to see what they have in mind and then look into how they operate so we get an idea of what it means to ‘prepare’ for the future.  We need to know what that future is.

4 scenarios, based on 2 axes.  Strong versus weak political and economic alignment axis and low versus high adaptive capacity axis.  The scenarios are presented around a hypothetical case to see its effects yet are presented as past events to create ‘lessons learned’.  So the document was written in 2010 and presents a futuristic +/- 2025, looking back at the past 15 years.  I’ll only cover the 2 with strong alignment as the other 2 are just full on doom scenarios with disaster and high cost. They’ll be going for strong alignment anyway.

Hack Attack (weak alignment, low adaptive)

An economically unstable and shock-prone world in which governments weaken, criminals thrive, and dangerous innovations emerge

Smart Scramble (weak alignment, highly adaptive)

An economically depressed world in which individuals and communities develop localized, makeshift solutions to a growing set of problems

Lock Step (strong alignment, low adaptive)

A world of tighter top-down government control and more authoritarian leadership, with limited innovation and growing citizen pushback

  • A pandemic causes harm to the economy through immobilization
  • Containment protocols save lives
  • Quick, strong mandatory enforcement of restrictions is the best way to recuperate
  • Leaders flexing their authority, imposing airtight rules & restrictions, mandatory mask wearing, body-temp checks everywhere
  • Leaders took a further grip on power, people gave up privacy and freedom for more safety and stability
  • Biometric IDs, tighter regulation of key industries, enforced cooperation slowly but steadily restored order and economic growth
  • Irresponsible authoritarian regimes fared far less
  • Virulent nationalism forms a threat
  • Strong technology regulation stifled innovation, high cost curbing adoption
  • Developing countries remain behind as they can only access ‘approved’ technology
  • In the developed world, the many top-down rules and norms greatly inhibit entrepreneurial activity, national interests holds back true scientific breakthroughs
  • The imposed control clashes with individual interest of the population leading to pushback and protests, even leading to overthrowing governments

Technology in ‘lock step’ is government driven and focused on national security, health and safety

  • scanners at airports detecting ‘antisocial’ behavior
  • smarter packaging for food and drinks
  • health screening required before discharge from hospital or prison
  • tele-presence technologies
  • protectionism-driven fragmented IT networks, governments policing internet traffic

Life example in ‘lock step’ tells the story of how traditions have to be given up for a better, cleaner world.  For example, for the river Ganges it has become illegal to bathe, dump waste, bury death into the river which allows the river to become pure again through additional support of water filtering devices along its shore.

Clever Together (strong alignment, highly adaptive)

A world in which highly coordinated and successful strategies emerge for addressing both urgent and entrenched worldwide issues

  • A flourishing world creates environmental challenges with increasing climate stability causing climate disasters and economic damage
  • Highly coordinated worldwide strategies are required to address the problems.  It requires system thinking and system acting on a global scale.
  • Carbon capture processes, cap and trade system, smart grids and other technologies lead to lowering of CO2
  • Inspired by this success, the global coordination is also put into action for disease and technology standards
  • Supported by transparency, data collection, processing and feedback
  • Enormous benign sousveillance allows data access anywhere for anyone
  • Nations have to give up some of their power to regional and international authorities
  • These international bodies lay the foundation for improving global and participatory problem solving and raising standards of living globally solving hunger, disease and access to basic needs
  • Better medical diagnostics, vaccines for better health outcomes
  • Pharmaceutical companies open up intellectual property
  • Energy, water, food are the major areas that require innovation to improve the living standards
  • The developing worlds improve through infrastructure, driving mobility and trade
  • Much of the growth is enabled through cleaner, green energy
  • Such prosperity still faced food scarcity as the population growth was further supported

Technology in ‘clever together’ is through strong global cooperation, spread in all directions, cheaper and wide availability.  Massive datasets to improve financial and environmental resources

  • cheap nanosensors and smart networks
  • intelligent electricity, water, transport in urban areas with internet access as a basic right
  • A malaria vaccine saves millions of lives
  • low-cost mind-controlled prostethics
  • Solar is used for everything through advanced solar-efficiency
  • mobile payment drives rapid economic growth in developing countries while developed worlds are hampered by banking interest and regulation

Life example in ‘clever together’ tells a story of how growing meat in a lab is contributing to a better planet

In summary, these scenarios tell us the following desires to achieve and issues to protect against:

  • World population growth is an issue
  • Climate crisis needs to be prevented
  • Food availability and quality needs to be improved through technology and manufacturing
  • Energy efficiency needs to be increased
  • A governing body on top of national governments is required with these national governments giving up some of their powers
  • This governing body is a cross-over between private and public organizations without a clear separation between them.  These private organizations include, if not primarily exist of, multinational companies
  • Vaccination should be used as a means to prevent and cure disease
  • Technology is key and innovations to improve technology is achieved through making knowledge open and freely accessible
  • Strong authoritarian decision making is required but the population may resist
  • Privacy has to be given up for the sake of transparency
  • Pharmaceuticals have a key role in improving healthcare
  • Sousveillance is pervasive everywhere, everything will be monitored, controlled and decided upon
  • Usage of resources will be ‘smart’

That is quite an agenda.  

Vaccines have received special attention because they are thought to cure many different issues.  HIV, cancer, heart disease, respiratory afflictions and many more as stated by Robert Langer, founder of Moderna and developer of the mRNA delivery technology. 

https://eu.news-press.com/story/news/coronavirus/2022/02/24/moderna-co-founder-robert-langer-not-surprised-vaccine-doubts/6898312001/

Cancer mRNA vaccination technology is already running human trials

https://www.fiercebiotech.com/biotech/merck-cuts-ties-modernas-early-phase-kras-vaccine-leaving-mrna-specialist-mull-next-steps

And HIV mRNA vaccines are being tested with promising results in animals

https://www.nih.gov/news-events/nih-research-matters/experimental-mrna-hiv-vaccine-shows-promise-animals

They want to reshape agriculture towards factory produced food in order to further improve the nutritional shortages of the crops as they grow too fast and on depleted soil, rendering an inferior nutritional value.

Now that we have an idea of what they are striving for, let’s have a look at how they want to put this world view in place and then see how they are doing so far.

Massaging the future

How do you tune governments across the world to implement your ideas?  You ‘educate’ them early on.  I have the impression Klaus Schwab got inspired by Hitler’s approach.  Being affected by WWII perhaps he tried to understand the history of how it evolved.  

Hitler wrote in his 1920 book “Mein Kampf” that those who control the children, control the future.  From age 10, they had to join the Jungvolk (Young people) and at age 14 promoted to Hitler Youth.  Girls followed the trajectory of Jungmädel to the League of German Girls.

Hitler hoped that “These young people will learn nothing else but how to think German and act German. . . . And they will never be free again, not in their whole lives.”

https://www.facinghistory.org/holocaust-and-human-behavior/chapter-6/joining-hitler-youth

Within the WEF, Klaus Schwab established the “Global Leaders of Tomorrow” academy in 1992.  In 2004 this was renamed to the Young Global Leader (YGL) academy.

http://pharos.stiftelsen-pharos.org/world-economic-forums-young-global-leaders/

The purpose was to recruit young personalities with potential, those who show entrepreneurial or political engagement early on in life.  They are then presented with a training at Harvard to learn and execute the WEF ideology.

Or in the words of Hitler: “These young people will learn nothing else but how to think like Klaus Schwab and act like Klaus Schwab

YGL, must be under 38 and serve 6 years.  A grooming club of the WEF for all politicians, royals and corporate to think alike.

As mentioned, Harvard provides the education of the YGL:

Young Global Leaders: Global Leadership and Public Policy for the 21st Century

Faculty Chair: Iris Bohnet, Professor of Public Policy, and Director, Women and Public Policy Program

This Program is designed to prepare the World Economic Forum’s select Young Global Leaders (YGL) to expand their knowledge base in order to better address some of the most pressing global problems. The course seeks to provide YGL’s with a deeper understanding of public policy issues in conjunction with leadership skills. Participants think more deeply about the major issues facing future generations and acquire the leadership skills necessary to effect significant change.

The program curriculum integrates theory and practice, emphasizing the advanced skills and knowledge necessary to serve as a powerful force for progress. Each session is tailored to challenge its unique group of Young Global Leaders and is led by expert senior faculty. The program focuses on critical global policy areas, with an emphasis on implementing innovative solutions in dynamic, multiple-stakeholder arenas.

Young Global Leaders committed to addressing the most pressing issues facing our world today are invited to attend this program.  Participation in the program is by invitation only.

This program is the result of a partnership between Harvard Kennedy School and the World Economic Forum. It is made possible through the generosity of David Rubenstein of The Carlyle Group, The Bill & Penny George Family Foundation, Marilyn Carlson Nelson, and Howard Cox, Jr.

https://wappp.hks.harvard.edu/young-global-leaders-global-leadership-and-public-policy-21st-century

If you already start to feel a bit uncomfortable about it and turn skeptical, Klaus Schwab is open and proud about it.

  • Angela Merkel (germany)
  • Tony Blair (UK)
  • Boris Johnson (UK)

were all YGL before, stated by Klaus Schwab himself

  • Angela Merkel
  • Vladimir Putin
  • Trudeau and half of his cabinet
  • President of Argentina and half of the cabinet
  • Macron and also half of the cabinet in France

all YGL graduates, stated by Klaus Schwab himself

The people who went through this YGL academy is reaching several thousands.  Below is a list of those uncovered so far.  Most can even be found on the YGL website.

2005

  • Ali Babacan, 8 times Bilderberg visitor, Turkish politician.
  • Ed Balls, British Labour Party politician who was an MP from 2005 to 2015. He is married to fellow politician and WEF/Young Global Leaders participant Yvette Cooper.
  • Marc Benioff,  founder, chairman and CEO of Salesforce, an enterprise cloud computing company. He is the owner of Time Magazine, which he bought for $190m and uses for political propaganda. Salesforce is one of the very central companies in the COVID deep event.
  • Sergey Brin, co-founder of Google.
  • Yvette Cooper, British Labour Party politician who is the Member of Parliament (MP) since 1997 and is married to fellow Labour politician Ed Balls.
  • Niall Ferguson is a Bilderberger historian. Ferguson charges between $50,000 to $75,000 to hold standard speeches, mostly to corporate executives.
  • Chrystia Freeland, Canadian politician. Deputy Prime Minister of Canada from 2019, including when the country introduced vaccine passports.
  • Austan Goolsbee, American economist. Professor of Economics at the University of Chicago‘s Booth School of Business.
  • Larry Page, co-founder of Google.
  • Haakon Magnus, heir apparent to the throne of Norway.
  • Paul Meyer – Co-founder and Chief Executive Officer of The Commons Project, which has build a worldwide interoperable system of vaccine passports, funded by the Rockefeller Foundation. Former Senior Fellow at the Markle Foundation, which has close ties to US intelligence services. Also selected in the predecessor program in 2003.
  • Mellody Hobson, president and co-CEO of Ariel Investments, wife of filmmaker George Lucas.
  • Gavin Newsom, governor of California in January 2019, a state in the forefront in driving the COVID deep event. Decreed mandatory COVID-vaccinations for all schoolchildren in 2021.
  • Samantha Power also attended the WEF/Global Leaders for Tomorrow 2003, so she is a reliable hand.
  • Nathaniel Rothschild, the only son and heir apparent of Jacob Rothschild
  • Mikheil Saakashvili, President of Georgia in 2008. CIA client.
  • Ferit Şahenk is a Chairman of Turkey’s Doğuş Holding conglomerate and richest person in Turkey.
  • Mabel van Oranje is a Dutch deep state fixer with an incredible CV.

2006

  • Joe Hockey, Australian politician and diplomat. Even with getting a push from the right place, he never made it to the top.
  • Ivan Krastev, a protegé of George Soros. Attended the Bilderberg for the first time in 2019.
  • Saif al-Islam Gaddafi, the second son of late Libyan leader Muammar Gaddafi. Attended at a time when the West was faking rapprochement.
  • Sergei Guriev, Russian economist, a professor of economics living in France.
  • Shami Chakrabarti, later Baroness Chakrabarti, a barrister involved in human rights who was appointed UK Shadow Attorney General by Jeremy Corbyn.
  • Justin Forsyth is a former Special Adviser to Prime Ministers Tony Blair and Gordon Brown.
  • Joshua Cooper Ramo is vice chairman and co-chief executive of Kissinger Associates.

2007

  • Andrew Ross Sorkin, American journalist working as financial columnist for The New York Times.
  • Enrique Peña Nieto was president of Mexico from 2012-2018. CIA?
  • Ian Bremmer, President and founder of the Eurasia Group. CFR, TLC, Bilderberg 2007
  • Jimmy Wales is an American Internet entrepreneur, best known as the co-founder of the online non-profit encyclopedia Wikipedia.
  • Karim Sadjadpour is a triple Bilderberger and “chief Iran analyst” at the International Crisis Group.
  • Kate Garvey is an English public relations executive and a former aide to British prime minister Tony Blair. She is married to Wikipedia co-founder Jimmy Wales.
  • Peter Thiel, billionaire member of the Bilderberg Steering Committee.
  • Rajiv Shah was employed at the Bill and Melinda Gates Foundation for seven years before he started working for the government (USAID), before then moving on to the Rockefeller Foundation.
  • Sheryl Sandberg, Chief Operating Officer of Facebook.
  • Siamak Namazi, an Iranian-American academic and business consultant who was sentenced to 10 years prison in Iran in 2016 for “collaboration with hostile government”.
  • Peter Bisanz Works for the World Economic Forum on creating an Universal Curriculum on Values that will encompass a full spectrum of socially relevant media, from Television to the Internet.

2008

  • Ellana Lee is Senior Vice President & Managing Editor, Asia Pacific, for CNN International.
  • Mark Leonard founded the European Council on Foreign Relations on behalf of George Soros.
  • Rory Stewart, named as MI6, was Chair of the international deep state/intelligence gorup Le Cercle from 2013-2015.
  • Susan Athey is the Economics of Technology Professor at Stanford Graduate School of Business.
  • Thomas Buberl is a money manager who first went to the Bilderberg in 2017.

2009

  • Alexander Stubb, Finnish politician who served as the Prime Minister of Finland from 2014 to 2015
  • Boris Nikolic is Bill Gates’ former science adviser. Named as one of the three executors of Jeffrey Epstein’s estate.
  • Dambisa Moyo is an economist who worked for two years at the World Bank and eight years at Goldman Sachs before becoming an author and international public speaker.
  • François Philippe Champagne, Canadian politician, lawyer and businessman. Bilderberg 2018 and 2019.
  • Jo Cox was a UK Labour Party politician. Brutally murdered on 16 June 2016.
  • Parag Khanna is an international thinker paid by multiple think tanks to promote technocracy.
  • Mark Zuckerberg, US billionaire credited with starting Facebook.
  • Stéphane Bancel, CEO of Moderna
  • Felix Maradiaga, a US-trained political operative who played a major role in the failed 2018 Nicaragua coup attempt.

2010

  • Julian Castro, US politician who was a prospective candidate in the US/2020 Presidential election.
  • Gabrielle Giffords, US politician who survived an assassination attempt in 2011. Resigned from office, but still in Democratic party leadership.
  • Ben Goldsmith, English financier and environmentalist, son of James Goldsmith.
  • Tomáš Pojar, Czech diplomat.
  • Philipp Rösler was German Minister of Health from 2009 to 2011.
  • Serpil Timuray, Turkish businesswoman working for multinational corporations.
  • Kevin Warsh is/was a member of the Bilderberg Steering Committee.
  • Dr. Sanjay Gupta, chief medical correspondent for CNN and fawning interviewer of Bill Gates. Played a big role promoting the official narrative of COVID-19

2011

  • Dawood Azami,  broadcast journalist and academic, working as multi-media editor at the BBC World Service.
  • Christa Markwalder is a Swiss politician who attended the 2016 Bilderberg meeting.
  • Max Levchin founded PayPal in 1998 with Peter Thiel.
  • Chuka Umunna is a British Labour politician who later went over to JPMorgan Chase and Edelman.
  • Nikki Haley, later became United States Ambassador to the United Nations.
  • Dana Perino was one of 4 White House Press Secretaries under George W. Bush.

2012

  • Huma Abedin , termed the effective “right-hand woman” of Hillary Clinton.
  • Jonathan Adiri,  Israeli businessman working in the digital healthcare sector, an area pinpointed as a priority by the World Economic Forum.
  • Henrique Capriles is a part of one of Venezuela’s wealthiest families. Presidential candidate 2012 and 2013. He and his party, supported by the National Endowment for Democracy, also participated in the 2002 coup attempt.
  • Brendan Cox is a former Special Adviser to Prime Minister Gordon Brown. His wife Jo Cox, MP for Batley and Spen, was murdered on 16 June 2016.
  • Daniel Bahr, German politician and member of the FDP. From May 2011 to December 2013 he was Federal Minister of Health, one in a series of German health ministers who were selected a Young Global Leader.
  • Jane Burston is a British scientist specialising in climate change.
  • Martha Lane Fox. On the board of Twitter. Member of the UK Joint Committee on National Security Strategy. House of Lords COVID-19 Committee.
  • Matteo Renzi, Italian politician who served as Prime Minister of Italy from 2014 to 2016.
  • Natalie Rickli is a Swiss politician of the Swiss People’s Party. During the COVID-19 crisis, she proposed no further health care for the unvaccinated. Went on secret luxury holiday to the Maldives while forcing everyone else to stay in lockdown.

2013

2014

  • Catherine Howarth, British executive in the NGO sector and a board member of the Scott Trust, owner of the deep state organ the Guardian.
  • Dominique Anglade is a Canadian politician. She is a member of the Quebec Parliament from the Liberal Party. She attended the 2018 Bilderberg.
  • Jacinda Ardern, Prime Minister of New Zealand, for the Labour party. Her career having signs of being helped forward by deep state interests, she has inflicted some of the harshest measures on COVID-19
  • Jared Cohen, attended 2018 Bilderberg and 2019 Bilderberg. He is the CEO of Jigsaw (formerly Google Ideas) and an Adjunct Senior Fellow at the Council on Foreign Relations.
  • Rebecca Weintraub, Harvard professor who works for total vaccination of everyone in the world. To achieve that, “we need to change our playbook”…“And that’s going to include vaccine mandates.”

2015

  • Professor Adam M. Grant, attended the Bilderberg for the first time in 2019. He granted tenure at age 28 at the Wharton Business School of the University of Pennsylvania specializing in organizational psychology.
  • Naomi Koshi,  Japanese lawyer and former politician.
  • Ilona Szabó de Carvalho, Brazilian activist showered with attention and funding from “global leaders”. Her Igarapé Institute receives funding from Google, the British and Canadian embassies, USAID, Luminate, Open Society Foundations are more. Appealed to “global leaders” to do “everything in their power” to make Brazil adopt “more responsible COVID policies”.
  • Alexander De Croo, PM of Belgium during some of the hardest lockdowns in Europe.
  • Mustapha Mokass, developer of a vaccine passport system and others for the 4th Industrial Revolution “dear to WEF founder Klaus Schwab”.

2016

  • Emmanuel Macron is a French Rothschild banker turned politician who was sworn in as President of France on 14 May 2017. Played an active part in the COVID-19 deep event, especially the introduction of vaccine passports.
  • Sam Altman, an American tech-millionaire. He is the CEO of OpenAI, a company specialising in Artificial intelligence.
  • Lila Tretikov, vice president at Microsoft from 2018 and specialist in Artificial intelligence.
  • Poppy Allonby, head of BlackRock in EMEA (Europe, the Middle East and Africa) & APAC (Asia-Pacific). Blackrock is by far the biggest capital manager in the world.
  • Sam Altman, American tech-millionaire. He is the CEO of OpenAI, a company specialising in Artificial intelligence.

2017

  • Molly Crockett, an American neuroscientist who studies human morality, altruism and decision making. In 2015, she showed that drugs targeting serotonin and dopamine in the brain can change moral decision-making in healthy people.

2018

  • Albert Rivera, Bilderberger and former politician who was the leader of the Spanish party Citizens from its founding in 2006 until 2019.
  • Leana Wen, American physician and former President of Planned Parenthood. She distinguished herself during the COVID-19 deep event by wanting to make the life of “unvaccinated” a living hell.
  • Alexander Soros, son of George Soros and Deputy Chair of the Open Society Foundations.

2019

  • Peter Buttigieg, US politician. He was a prospective candidate in the US/2020 Presidential election. He is United States Secretary of Transportation since February 3, 2021.
  • Matthew Guilford, Co-Founder and Chief Executive Officer of Common Health, a part of the The Commons Project. Its digital health system to allow sharing of data about a person’s clinical history and status. “Sharing of COVID-19 test results and vaccination records is a natural role for CommonHealth.”[3]
  • Yalda Hakim, Australian/British broadcast journalist, news presenter, and documentary maker.
  • Clare O’Neil, Australian politician. In 2019 she was considered a frontrunner for the deputy leadership during the 2019 Australian Labor Party leadership election.
  • Carlos Alvarado Quesada, President of Costa Rica, in November 2021 the first country to mandate COVID-vaccines for children.
  • Daniel Crenshaw – Congressman from Texas (R), 2nd District, United States Congress[4]

2020

  • Megan Rapinoe – co-captain of the US women’s soccer team, Rapinow lifted the 2019 FIFA World Cup. Off the field, she advocates for gender equality, including equal pay in her sport, and speaks out on diversity and inclusion.
  • Jesús Cepeda – Chief Executive Officer of OneSmart City, a company that uses blockchain and artificial intelligence to help city authorities provide digital services.
  • Jack Conte – an American businessman and founder of Patreon, which has been busy blocking funds to independent media for many years.
  • Larry Madowo – The BBC Africa Business Editor launched of six new business TV shows for African audiences in English, French and Swahili. Madowo is also an on-air correspondent on BBC radio and television and has reported from more than 40 countries.
  • Sanna Marin – Marin held her first political post at the age of 27. Despite a total lack of experience, she was Finland’s Prime Minister during the COVID-19 crisis.
  • Annalena Baerbock – German politician serving as the co-leader of Alliance 90/The Greens. Favourite of the German mainstream media for Chancellor of Germany.
  • Alicia Garza, Co-founder of Black Lives Matter, Garza is a US civil rights activist and editorial writer influential on issues of health, student rights, rights for domestic workers, and campaigns against police brutality, racism, and violence against gender non-conforming people of colour.
  • Kristo Kaarmann – Co-founder and CEO of TransferWise, a peer-to-peer money transfer business which aims to allow people to access the real mid-market exchange rate by cutting out traditional banking fees.
  • Akiko Naka – Founder and Chief Executive Officer of Wantedly, a social networking service for professionals, Akiko was the youngest female founder ever to take a company public in Japan.
  • Yetnebersh Nigussie – An Ethiopian human rights lawyer who pushes for women’s and girls’ rights and inclusive education.
  • Gaurav Gupta – Co-Founder and Chief Operating Officer of Zomato, an Indian restaurant aggregator and food delivery start-up. He launched the table reservation business and scaled it up across India, the United Arab Emirates and Australia.
  • Henry Motte-Muñoz – Founder and CEO of Edukasyon.ph, which says it is the largest youth platform in the Philippines, empowering more than 10 million student visitors each year to find their path from education to career.

2021

  • Andrew Bragg, Australian politician. He became a Senator in 2019.
  • Adriana Cargill is a member of the Cargill family, the fourth-wealthiest family in America. She works as a journalist in Los Angeles at KCRW Radio.
  • Vera Daves de Sousa was made finance minister of Angola when she was 35.
  • Amélie de Montchalin is a French politician. She has served as a minister under President Macron, responsible for implementing the pass sanitaire in public services.
  • Garlin Gilchrist II is an American politician. He has been Gretchen Whitmer’s deputy since 2019.
  • Ibram X Kendi is an American author and activist. He believes the low take-up of Black people having the COVID vaccine is due to racism.
  • Devi Sridhar is a Professor and Chair of Global Public Health at the University of Edinburgh. In 2020, she advised the Scottish government on how to deal with the COVID-19/Pandemic.
  • Vasudha Vats is a Vice president of Pfizer.

https://www.informedchoiceaustralia.com/post/wef-and-their-young-global-leaders-program

Bilderberg is a similar gathering place where ideas are discussed and alignment is achieved.  Several of the YGL are also connected with Bilderberg giving rise to the idea that many of these global think tank clubs share a similar philosophy.

The impressive list of big tech, big capital, big pharma, royals, high position politicians shows a successful ‘Jungvolk’ implementation across its 30 years of existence.

It doesn’t stop with educating YGLs.  As an example, below is a list of Canadian participants to the WEF events showing that it is not only through its YGL academy but also via directly reaching out to people of high interest.  In the words of Klaus Schwab: “penetrate the cabinets”.

What is wrong with it?

Genuinely you may ask, what is wrong with it?  Understandably it is overwhelming and all may seem well intended at first sight but there truly are issues with it.

Critically looking at the above presented information we notice a couple of things.

  1. It envisions a totalitarian control.  This means that democracy is eliminated.  It doesn’t matter who you vote for, the national government takes its directives from the higher up governance level.
  2. Whatever actions they plan, the size of the population must decrease.  Who will live and who won’t?  Who decides and who will be affected by it?
  3. With such a governance in control, they will decide who can do what.  Autonomy will be lost
  4. The individual persons will have to give up their privacy and submit to their control
  5. The multinationals will cooperate and fulfill the demands of the global governance, not the demands of the population
  6. Social media platforms will intervene in the information to align the public, trying to avoid social unrest.  Fact-checking, accounts blocked, content taken off-line.. in other words pure censorship in service of the ideology 
  7. Even if you assume nothing but goodness in that ideology, it relies on multinationals.  These companies are run by highly competitive, profit-first management who have a track record of breaking the law for their own gain
  8. These YGL are pushed forward into leading roles without having the full life experience to make carefully balanced decisions in the best interest of the population.  Rather they are programmed to execute the ideology and will have a hard time listening to the voice of the population.

Our freedom is going to be curtailed via technology with the introduction of a digital ID and a digital currency.  Of course both under control of the totalitarian globalist regime.

With their big data and AI, all your choices, actions, thoughts, political ideas will be captured and screened to see who is aligned and who is not.

With the digital currency, they want to make it programmable so that they can control on what you can spend money.  In essence it will no longer be money but authorization.

The highest leverage of this control can be obtained when nobody owns anything anymore and everybody makes use of subscriptions.  This makes you fully dependent and by controlling the subscriptions they can decide who can participate in society and who doesn’t.

This is the non-violent implementation of dictatorship.  As we are witnessing today once more, you can become violent against a country to dictate compliance or you can isolate and disable a country to dictate compliance.  It works equally well at the individual level.

Examples

To show that these negative effects exist, we can look around to see what is happening.

PM Justin Trudeau

An example of the drive from these inexperienced YGL is Trudeau.

Zero tolerance for who gets into the way.  Framing, stigmatizing those who oppose you, divide and conquer.  How did he get into position and where does he get the idea from that there is nothing wrong with his behavior?

Something that didn’t go unnoticed by others.

His [Trudeau] comments prompted People’s Party of Canada leader Maxime Bernier to call Trudeau a “fascist psychopath.”

https://westernstandardonline.com/2021/12/trudeau-calls-the-unvaccinated-racist-and-misogynistic-extremists/

Not a single reaction from other countries about the atrocities of Trudeau.  Is it any wonder when they all come from the same club?

Legislation

One other example is Jacinda Ardern, Prime Minister of New Zealand.  And yes, also a YGL that  does not have a sense of what individual liberty and human rights mean.  They care about the program that they were indoctrinated with.  Because they are young, they are inexperienced and take unthoughtful, unbalanced decisions.  

Group think makes them uneasy to criticize what they were teached, it makes them followers.  As a loyal follower, she wanted to make vaccination mandatory by law.  Luckily their supreme court ruled such a law was an unjustified incursion on the Bill of Rights.  In the picture below we see her next to Bill and Melinda Gates.  “A pat on the back for doing so well, my young apprentice.”

https://www.nzherald.co.nz/nz/not-demonstrably-justified-high-court-upholds-challenge-to-police-and-nzdf-vaccination-mandates-terminations-suspended/LMAUM7LZWV6FFQWAKKJFLKYLIE/

In Belgium we see Prime Minister Alexander De Croo accepting mandatory vaccination for the medical staff.  And you guessed it, he graduated in 2015 from YGL.

https://www.vrt.be/vrtnws/nl/2021/11/15/federale-regering-zet-licht-op-groen-voor-verlichte-vaccinatie-z/

He circled around mandating it at national level for everyone, not knowing which direction to go.

This mandatory vaccination has been orchestrated throughout the western world where most of the WEF and RF influence is most pervasive.

Vaccination

Bill Gates is an early graduate of the YGL and also a Harvard student.

https://news.harvard.edu/gazette/story/2013/09/dawn-of-a-revolution/

Pfizer and Moderna are 2 companies that received investment and are well connected to the WEF and Rockefeller.  The Bill & Melinda Gates foundation invested $20 million in Moderna to develop mRNA vaccination in 2016.  That same year, Moderna filed a patent for a genetic code.  This code has now been found in the spike protein of the SARS-COV-2 virus.  The scientists who discovered this claimed a 1 in 3 trillion chance of ending up in the spike protein.

https://www.dailymail.co.uk/news/article-10542309/Fresh-lab-leak-fears-study-finds-genetic-code-Covids-spike-protein-linked-Moderna-patent.html

In comparison, when particle physics does experiments, they want to reach at least sigma 5 to rule out chance as much as possible before they accept the results in validation of the theory.  Sigma 5 corresponds to a 1 in 3.5 million chance.  This corresponds to a p-value of 0.0000006.  In nutrition and medical research they are happy to reach a p-value of 0.05.

https://blogs.scientificamerican.com/observations/five-sigmawhats-that/

Obviously we need much more proof but it paints a picture whereby the virus is likely lab made in anticipation of a true virus but unfortunately has leaked out of the lab.  Gain-of-function research fits their worldly view in order to try and eradicate viral pathogens.  

The investment in vaccine technology surged after the 2010 publications of RF and WEF.

The leak rushed them with insufficiently tested vaccines.  Negative results would be downplayed and discovery discouraged because in their mindset, everybody must get vaccinated.  The WEF program must be executed, it is the only sensible thing to do.

Government leaders in key positions accept the risks, force vaccination to the maximum as possible through stigmatizing and isolating, disabling social abilities for those who refuse the vaccine. Because these leaders too are so brainwashed that they ignore the population and can only think about executing the WEF program, it is the only sensible thing to do.

Pfizer and Moderna, both financially supported by Bill Gates and the RF, are prime examples of altruism in multinational companies, so we see they are being sued for using patented technology on several fronts.  Pfizer failed to recognize scientists from the NIH as co-inventors they collaborated with.

https://www.reuters.com/legal/government/covid-19-patent-challenges-mount-moderna-faces-new-vaccine-lawsuit-2022-02-28/

In 2009, Pfizer payed the largest settlement in healthcare fraud. A whopping $2.3 billion but apparently that doesn’t hurt them.

https://www.justice.gov/opa/pr/justice-department-announces-largest-health-care-fraud-settlement-its-history

We now have to rely on whistleblowers in the hopes of getting a more transparent feed of information.  It doesn’t paint a neat picture if the FDA would have cooperated with Pfizer to massage the data to fit the narrative.  Something only possible when all individuals are in tune.

Needles to say, the influence of these large corporations is put to use for their own benefit at the cost of the population. A critical article summarizes the staggering reality of how they operate. Please read it in full, that is where the real dirt is, but here are a few quotes showing some familiar names.

Since then [2005], the WHO has accepted many financial contributions from big pharma. In fact, it’s only 20% financed by member states today, with a whopping 80% of financing coming from private donors. For instance, The Bill and Melinda Gates Foundation (BMGF) is now one of its main contributors, providing up to 13% of its funds — about $250–300 million a year. Nowadays, the BMGF provides more donations to the WHO than the entire United States.

“The big concerns are that the Gates Foundation isn’t fully transparent and accountable,” Lawrence Gostin, director of WHO’s Collaborating Center on National and Global Health Law, told Devex in an interview. “By wielding such influence, it could steer WHO priorities … It would enable a single rich philanthropist to set the global health agenda.

Take a peek at the WHO’s list of donors and you’ll find a few other familiar names like AstraZeneca, Bayer, Pfizer, Johnson & Johnson, and Merck.

Anyone wonders how to push the vaccine agenda when you are richer than most countries?

in 1992 they [CDC] found a loophole: new legislation passed by Congress allowed them to accept private funding through a nonprofit called the CDC Foundation. From 2014 through 2018 alone, the CDC Foundation received $79.6 million from corporations like Pfizer, Biogen, and Merck.

Dr. Anthony Fauci’s NIAID is just one of many institutes that comprises the NIH — and the NIH owns half the patent for the Moderna vaccine — as well as thousands more pharma patents to boot. The NIAID is poised to earn millions of dollars from Moderna’s vaccine revenue, with individual officials also receiving up to $150,000 annually

And a final one showing again the big flaw in the WEF and RF governance model.

“Corporations like Pfizer should never have been put in charge of a global vaccination rollout, because it was inevitable they would make life-and-death decisions based on what’s in the short-term interest of their shareholders,” writes Nick Dearden, director of Global Justice Now.

https://medium.com/@bexstrong/big-pharma-corruption-and-lawsuits-amidst-covid-vaccine-c734a494b776

And lately, some horrible effects start to float atop. A pathologist goes public claiming that they were told not to look for any evidence of deaths caused by vaccination.

Are the numbers of deaths possibly inflated, is the urgency overstated? Those who are at risk of ending up in the hospital or at risk of dying became apparent early on in the pandemic. A population wide vaccination did not make sense and should have been limited to those at risk. This would have been a much more efficient use of resources, a much lower impact on economy, a much lower impact on deaths from cancer, kept domestic violence from rising etc.

In a January 19, 2022, press conference, U.K. health secretary Sajid Javid admitted that the daily government figures are unreliable as people have been and continue to die from conditions unrelated to COVID-19, but are included in the count due to a positive test. He also admitted that about 40% of patients presently counted as hospitalized COVID patients were not admitted due to COVID symptoms. They were admitted for other conditions and simply tested positive.

The average age of death in the U.K. from COVID in 2021 was 82.5 years. Compare that to the projected life expectancy in the U.K., which is 79 for men and 82.9 for women.

In late August 2020, the CDC published data showing only 6% of the total death count had COVID-19 listed as the sole cause of death. The remaining 94% had had an average of 2.6 comorbidities or preexisting health conditions that contributed to their deaths. So, yes, COVID is a lethal risk only for the sickest among us, just as Walensky said, but that’s true whether you’re “vaccinated” or not.

Apart from inflated numbers, it could even be worse. Have we caused more people to die due to malpractice?

One investigation showed a staggering 80% of COVID-19 patients in New York City who were placed on ventilators died, causing some doctors to question their use. U.K. data put that figure at 66% and a small study in Wuhan found 86% of ventilated patients died. In an April 8, 2020, article, STAT News reported:

Without doubt, most of the early COVID patients were killed from ventilator malpractice, and patients continue to be killed — not from COVID but from harmful treatments. Mechanical ventilation can easily damage the lungs as it’s pushing air into the lungs with force.

An other source of inflating numbers can be because hospitals receive payment for:

  • COVID testing for all patients
  • COVID diagnoses
  • Admitting a “COVID patient”
  • Use of remdesivir
  • Use of mechanical ventilation
  • COVID deaths

For Remdesivir, studies show that 71–75% of patients suffer an adverse effect, and the drug often had to be stopped after five to 10 days because of these effects, such as kidney and liver damage, and death

Remdesivir trials during the 2018 West African Ebola outbreak had to be discontinued because death rate exceeded 50%

Yet, in 2020, Anthony Fauci directed that Remdesivir was to be the drug hospitals use to treat COVID-19, even when the COVID clinical trials of Remdesivir showed similar adverse effects.

Attorney Thomas Renz and a team of data analysts have estimated that more than 800,000 deaths in America’s hospitals, in COVID-19 and other patients, have been caused by approaches restricting fluids, nutrition, antibiotics, effective antivirals, anti-inflammatories, and therapeutic doses of anti-coagulants.

https://www.theepochtimes.com/the-truth-is-coming-out-about-covid-deaths_4309806.html?utm_source=ref_share&utm_campaign=tw&rs=SHRDLLKL

How can we trust these large corporations? They invested heavy money. They are not gonna relax and let it all go to waist. They can take the risks and pay fines, still ending up with considerable profit.

A critical report has gathered information on the pharmaceutical companies. You can pay special attention to the Pfizer and Moderna sections.

https://www.globaljustice.org.uk/sites/default/files/files/resources/pharma_covid-19_report_web.pdf

Another critical assessment is done in the following toxicology report titled “Why are we vaccinating children against COVID-19?”

The second issue is why the deaths shown on Fig. 2 were not predicted by the clinical trials. We examined the Pfizer trial results (based on a few months of testing) and did not see how (potentially) hundreds of thousands of deaths could have been predicted from the trials’ mortality results. Why this gap?

This allows spike protein to be manufactured/expressed in endothelial cells at any location in the body, both activating platelets to cause clotting and causing vascular damage. It is difficult to believe this effect is unknown to the manufacturer, and in any case, has been demonstrated in myriad locations in the body using VAERS data. There appears to be modest benefit from the inoculations to the elderly population most at risk, no benefit to the younger population not at risk, and much potential for harm from the inoculations to both populations. It is unclear why this mass inoculation for all groups is being done, being allowed, and being promoted.

We can’t say for sure that many/most died from COVID-19 because of: 1) how the PCR tests were manipulated to give copious false positives and 2) how deaths were arbitrarily attributed to COVID-19 in the presence of myriad comorbidities.

On the latter issue, both Virginia Stoner [85] and Jessica Rose [86] have shown independently that the deaths following inoculation are not coincidental and are strongly related to inoculation through strong clustering around the time of injection.

https://www.sciencedirect.com/science/article/pii/S221475002100161X

It should not be a surprise that companies are … well, companies are money making machines so Pfizer says we need an annual COVID vaccine, a subscription you could call it. Moderna and Novavax are already preparing for such a situation by combining COVID with the annual flu vaccine. This plan of a nice addition to their annual revenue stream goes against what the WHO envisions and asks them to do a better job with the vaccines so that they provide longer protection.

https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-ceo-sees-annual-covid-vaccine-rather-than-frequent-boosters-2022-01-22/

https://jamanetwork.com/journals/jama/fullarticle/2786818

https://www.dailymail.co.uk/health/article-10400077/WHO-warns-repeated-booster-shots-not-sustainable.html

Agriculture

Bill Gates’ execution of the plans also spreads towards the agricultural field.  The following article, worth a read, raises criticism on the untested spreading of GMO’s of which the consequences are unknown to animal and human health.  A similar approach here with patenting to protect the multinational corporations

Propaganda and corporate interest

In order to advance on the climate change agenda, Harvard, as a sound board of the WEF and RF, creates a continuous output of articles and epidemiological studies of doubtful quality to bring the message across for the population to start reducing meat intake.  Harvard is proud to influence and propagate the worldly view, held by its donator.

They have consistently put out more anti-(red-)meat messages coinciding with 2 events.  A first is the publication of the papers from WEF and RF in 2010 and a second time when Beyond Meat went public on the stock market.  A company backed by the WEF and RF plans.

If you still think this is all coincidental, perhaps you want to hear it from the globalists themselves?

Klaus Schwab transcript: “I created the community of global shapers.  As a means, as a force to shape our common future.  This engagement of the young generation [of global shapers] never has been more important than now where we have to face the consequences of the pandemic of covid 19.  For creating a more resilient, more sustainable and a more inclusive world.  You are calling for the international community to saveguard vaccine equity to respond to covid 19 and prevent future health crisis.  Nobody will be save if not everybody is vaccinated.  Young people, you, are rallying behind the global wealth stacks to manage the alarming search in wealth inequality.  You are calling for programs that help you and young progressive voices throwing (?) government and become policy makers.  To limit global warming, you are demanding to halt coal oil and gas exploration.  You are asking from us to replace any corporate …(?) directors, who is unwilling to transition to clean energy sources.  You are championing an open internet and a 2 trillion digital access plan to bring the world online and prevent internet shutdown.  And you are presenting new ways to minimize the spread of misinformation and you want to combat dangerous extremist fuse in the internet.  On “Stakeholder Capitalism” [a book written by Klaus Schwab] ‘you’ will be the key.”

In his book, Schwab writes: “It will also accentuate one of the greatest societal and individual challenges posed by tech: privacy. We will see how contact tracing has an unequalled capacity and a quasi-essential place in the armoury needed to combat COVID-19, while at the same time being positioned to become an enabler of mass surveillance,” arguing that the pandemic “will accelerate innovation even more” in this area.

https://thepostmillennial.com/cabinet-ministers-dodge-questions-on-trudeaus-ties-to-world-economic-forum

Deciding that the New Globalists needed a formal platforms to promote their ideas, David Rockefeller created the Trilateral Commission, and Klaus Schwab founded the World Economic Forum. These business clubs successfully co-opted members of the political elite, and together they have formed an engine room for policies, partnerships and programmes to extend the boundaries of market-led globalisation.

https://www.universitypressscholarship.com/view/10.7228/manchester/9781784992897.001.0001/upso-9781784992897-chapter-006

Just as a side note, David Rockefeller Jr also graduated from Harvard.

https://www.umsl.edu/hwec/WEArecipients/rockefeller.html

Needles to say, the influence of these large corporations is put to use for their own benefit at the cost of the population. A critical article summarizes the staggering reality of how they opperate.

https://medium.com/@bexstrong/big-pharma-corruption-and-lawsuits-amidst-covid-vaccine-c734a494b776

Digital ID

Ursula Von der Leyen, President of the European Commission, also a YGL graduate is at the forefront of introducing a European digital ID.  Such an ID is no longer under national control.

https://ec.europa.eu/info/strategy/priorities-2019-2024/europe-fit-digital-age/european-digital-identity_en

Central Bank Digital Currency

The EU also wants to implement CBDC.  This will be a programmable currency so that there is control on who, how and where it can be spent. Totalitarian control demanding obedience, for the greater good of course.

https://www.ecb.europa.eu/press/key/date/2022/html/ecb.sp220218_1~938e881b13.en.html

You own nothing

Ida Auken, YGL graduate of 2015 contributes to the vision with her own little story on the ideal.  A utopia with lack of realism, a recurrent theme in these young leader.

https://www.forbes.com/sites/worldeconomicforum/2016/11/10/shopping-i-cant-really-remember-what-that-is-or-how-differently-well-live-in-2030/?sh=3b52b3391735

This dream world has everything available as a service since you own nothing.  AI and robots perform most of the work so that more time can be spent with friends, family and leisure.  Privacy is completely lost but life is better.  Those who didn’t accept, live miserable lives outside of the cities.

How are these people making money?  Who builds all of these devices, the technology? Recycling of waste, the dirty jobs, digging for raw material.. Someone has to do the dirty work.

Natural Immunity

Nothing is wrong with corporations who want to sell us their products. But in a world that is supposed to be science driven, that science can become an inconvenient truth.

Science tells us that natural immunity is a much more potent weapon. So why don’t we go for a strategy of 1 vaccination + getting people infected? Why say we need a booster shot every year from now on and ignore what the studies are finding out?

This is how multinationals act and Klaus Schwab doesn’t know this? The Rockefeller Foundation doesn’t know this? They call themselves ‘elite’ yet don’t understand the impact of such actions upon the population? I refuse to be naïve.

Together, our data suggest that the additional antigen exposure from natural infection substantially boosts the quantity, quality, and breadth of humoral immune response regardless of whether it occurs before or after vaccination.

source: https://www.science.org/doi/10.1126/sciimmunol.abn8014

Naturally infected populations were less likely to be reinfected by SARS-CoV-2 than the infection-naïve and vaccinated individuals.

source: https://www.nature.com/articles/s41598-022-05325-5

Natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicits strong protection against reinfection with the B.1.1.7 (alpha),1,2 B.1.351 (beta),1 and B.1.617.2 (delta)3 variants.

source: https://www.nejm.org/doi/full/10.1056/NEJMc2200133

Seroconversion after SARS-CoV-2 infection confers protection against reinfection lasting at least 8 months.

source: https://academic.oup.com/cid/article/74/4/622/6287116?login=false

These data suggest that naturally acquired SARS-CoV-2 immunity does not wane for at least 10 months post-infection

source: https://onlinelibrary.wiley.com/doi/10.1002/rmv.2260

Anti-RBD levels were observed after a positive COVID-19 test result up to 20 months, extending previous 6-month durability data.5

source: https://jamanetwork.com/journals/jama/fullarticle/2788894
source: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780557

The study results suggest that reinfections are rare events and patients who have recovered from COVID-19 have a lower risk of reinfection. Natural immunity to SARS-CoV-2 appears to confer a protective effect for at least a year, which is similar to the protection reported in recent vaccine studies.

source: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780557

Vaccination of previously infected individuals does not provide additional protection against COVID-19 for several months, but after that provides significant protection at least against symptomatic COVID-19.

source: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac022/6507165

On the other hand, protection through vaccination alone starts to wane after a few months. So doesn’t it make sense to get a single vaccination and then let the population mingle to obtain a natural infection from the virus so that a more robust long-term protection is achieved?

I’m no expert of course and I’m also not a multinational globalist who tries to profit from a lifetime medical subscription.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00089-7/fulltext

We, the people

All the above are show cases of how these corporations and ‘elite’ individuals are preparing for the future.  Multinationals get bigger and more powerful.  They get away with damage, lawsuits and still make profit without having to change their modus operandi.  The population takes casualties and falls victim, losing power, influence, privacy and freedom.

The elite can hide what is really going on while the population has to stand with their pants down, butt naked.

The big picture of these multinationals is to drive consumption from the products and services of the ventures that they invested in.  Greed, profit, power… pure and simple, business as usual.  This is not the way the world is going to improve for the population.

How can we trust a world in which we are being lied to?  A world where the truth is hidden from us.

The democratic foundation of the government serving the people is swept away and replaced with the people serving the globalists.

Messing around with mRNA is inherently unsafe.  mRNA in the body will translate into protein.  Protein have a function, they will interact within the body.  These interactions are hard to predict and can be both positive and negative.  The complexity within our bodies is so huge that only direct and severe issues are noted simply because they cannot be ignored if you don’t close your eyes to it.  In addition, the variety of our population and health state creates another set of complexities that is hard to investigate.

One other argument is that these new mRNA segments may offer more recombination possibilities for viruses leading to further unexpected mutations.

It’s not the vaccination delivery method we should be worried about, it is the effect of the mRNA once it is in our body.

Such technology and accompanying responsibility will be put in the hands of who exactly?

We, the psychopaths

Maybe by now you think who is crazy enough to want all of this?  I started to notice a number of traits:

  • central and high level of control
  • selfish benefitting
  • demanding subordinate obedience
  • manipulation to buy into their vision
  • collateral population damage is a necessary and tolerated side effect of meeting the goals

The characteristics of psychopathic behavior started to emerge.  Is it possible that this is all the result of a psychopathic tendency to get to the maximum of power grabbing and benefitting at the cost of others?

The following is a quote from the article (below the quote) discussing how psychopathic leaders behave. 

People with psychopathy crave power and dominant positions, experts say. But they are also chameleons, able to disguise their ruthlessness and antisocial behavior under the veneer of charm and eloquence. In the most extreme, clinical, cases those traits have allowed serial killers to elude capture.

One route to grabbing power for the highly intelligent psychopath is to climb the corporate ladder. There is a real chance that at some point a chief financial officer will be confronted with a psychopathic boss. Roughly 4% to as high as 12% of CEOs exhibit psychopathic traits, according to some expert estimates, many times more than the 1% rate found in the general population and more in line with the 15% rate found in prisons.

the former [psychopath] is not detached from reality but lacks empathy and doesn’t care about the consequences of his or her actions. Psychopaths are generally considered intelligent, manipulative and charming – and lack the ability to learn from mistakes or punishment.

“They don’t care that they are hurting you. They will do what they have to do.”

People with these traits are good at “impression management” and know how to get people to like them, she says.

“The Psychopathic CEO” https://www.forbes.com/sites/jackmccullough/2019/12/09/the-psychopathic-ceo/?sh=3cc06f84791e

“How Sociopathic Capitalism Came to Rule the World” https://www.theatlantic.com/business/archive/2016/11/sociopathic-capitalism/506240/

Harvard, who is an active contributor to the globalists plan does recognize the psychopathic behavior of these leaders.  A little detail they forgot to include in the world view?

“Executive Psychopaths” https://hbr.org/2004/10/executive-psychopaths

Perhaps it is a trait of psychopaths to ignore this or they find it exciting and challenging to be among their peers?  Are we going to be run by a club of psychopaths?  

It is not inconceivable that in order to become a multinational, you must have a leadership with at least some psychopathic tendency.

I’m not alone in this thinking.  The organization “Grand Jury, the court of Public Opinion”, a group of global attorneys and lawyers who want to address crimes against humanity in a simulated court.  They too have puzzled the underlying plans together summarized in 4 distinct facts:

Starting at 19:28 (Reiner Fülllmich)

  1. There is no Corona pandemic but only a PCR-test plandemic, designed to create a constant state of panic among the world population.  Designed by a group of sociopathic, psychopathic people who love and fear people at the same time, no empathy and the desire to gain full control.
  2. Effective treatments were banned in favor of vaccination, despite being unsafe and even exceptionally lethal
  3. Changed the definition of pandemic to create a corona pandemic
    1. At 22:48: they have taken over our governments through their own WEF YGL.  YGL started in 1992 of which Angela Merkel and Bill Gates were one of the first graduates.
  4. Their main goal is to obtain full and complete control including population control which requires a massive reduction of the population, manipulation of the population through the help of mRNA injections, destruction of democracy, losing our culture and identity.  A digital passport monitoring and controlling each and every move and one digital currency that can only be received from one world bank, theirs (the elite).

https://odysee.com/@GrandJury:f/Grand-Jury-1-EN:0 ; https://grand-jury.net/

Neil Oliver (GB News) gave a speech sharing the same insights

https://mobile.twitter.com/GBNEWS/status/1497664641966780416

A transcript of how they think: “At Davos, a few years ago the … survey showed us that the good news is the elite across the world trust each other more and more, so we can come together and design and do beautiful things together.  The bad news is that in every single country they were polling, the majority of people trusted that elite less”.

Psychopats fail to see what they are doing wrong. I’m sure the polling results came as a surprise.

I cannot help but think that the whole plan fits so well in how a psychopath would dream about it and approach it.  Their failure to see how the public is affected, their proudness of what they aim for and are achieving, the acceptance of collateral damage without a blink.  Such ‘leaders’ should not unite.  The moment when someone sensible looks back and thinks “oh my god, what have we done”, it will be too late.

Perhaps “very intelligent psychopaths in philanthropic disguise” sums up the bunch.
It is time the global population shouts a united “You’re fired!

– – – T H E – E N D – – –

Cerebral glycogen levels influence endurance capacity

A recent paper was published in which Timothy Noakes PhD reviewed current evidence on what sustains endurance and came to the conclusion it is not based on muscle fatigue but rather on something unknown that does involve the brain.

“What Is the Evidence That Dietary Macronutrient Composition Influences Exercise Performance? A Narrative Review” https://www.mdpi.com/2072-6643/14/4/862/htm

When you are exercising and in case of endurance for several hours, where is that movement coming from? These muscle twitches that sustain the activity are generated by electrical impulses coming from the brain, transferred through the nerves.

These electrical impulses require energy, more energy than when you are sedentary. This means that if the higher energy demand cannot be sustained, these electrical impulses will not be sustainable and result in a reduced capacity to twitch, thus lower power and therefor also reduced movement.

This blog is focusing on the brain but also keep in mind that in the muscle itself there are elements to induce fatigue so do not think fatigue is only about the brain.

Instead of repeating much of what is covered in the following article, I suggest you read it directly as it covered exactly the point of fatigue and brain glycogen levels.

“Endurance and Brain Glycogen: A Clue Toward Understanding Central Fatigue” https://link.springer.com/chapter/10.1007/978-3-030-27480-1_11

Brain glycogen is used as a source of lactate production in the brain to support the endurance activity.

Isoglycemic brain fatigue

I would like to add onto that paper because it suggests that blood glucose levels result in this ‘central’ fatigue while there is also evidence of this fatigue despite maintaining glucose levels which Noakes showed in his review.

In order for the brain to suffer in its capacity despite sufficient plasma glucose, the energy consumption must be higher than what the brain can get from circulation.

During endurance exercise, the brain increases its uptake of lactate from circulation depending on availability.

Looking at glucose, there is only a small difference in uptake.

But we have to be careful with interpretation. A better indication of what is going on is via the metabolic rate. Is the brain metabolizing more glucose? The following graph shows that there is no difference, no trend with changing arterial supply of glucose.

Looking at lactate, the increase from rest to exercise shows a 0.55 mmol difference.

And for lactate we do see a nice correlation between uptake and metabolism based upon supply.

“Cerebral glucose and lactate consumption during cerebral activation by physical activity in humans” https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.11-183822

What this shows us is that the additional energy requirement for endurance capacity is driven by lactate in the brain, not by glucose. That does not mean that glucose doesn’t contribute in the brain to lactate. It is possible that a proportion of it is converted to lactate through glycolysis but that proportion seems constant across resting and exercising conditions.

The effect of utilizing lactate is that it spares glucose.

“Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion” https://physoc.onlinelibrary.wiley.com/doi/10.1113/jphysiol.2002.027128

This puts everything in a very different picture. The brain is happy with glucose but doesn’t consume more than needed and instead makes use of the available lactate. Happy or is it protecting itself from too much glucose? (see GLP-1)

Yet in order to have lactate available in circulation, the skeletal muscle are the source.

GLP-1

Glucagon-like-peptide 1 is a hormone that is secreted from the intestines. The effect of GLP-1 shows that it reduces glucose uptake in the brain. When we eat carbohydrates, the resulting excess glucose in the blood could potentially increase the supply to the brain but GLP-1 is preventing this. Again it seems that the brain requires a certain supply but will not make use of more than what is required.

“Glucagon-Like Peptide-1 Inhibits Blood-Brain Glucose Transfer in Humans” https://diabetesjournals.org/diabetes/article/57/2/325/13136/Glucagon-Like-Peptide-1-Inhibits-Blood-Brain

Back to our question on fatigue despite sufficient glucose in the blood… If lactate fuels endurance capacity in the brain then it is not surprising that adding carbs via ingestion to raise plasma glucose do not support the brain. However, the quantity ingested may even work detrimental as GLP-1 may reduce brain glucose uptake gradually leading to a brain energy shortage as the athlete continues to ingest glucose.

A plausible reason is that increased uptake of glucose and resulting metabolism is detrimental to heat production. This is likely also the reason why fatty acid metabolism is minimal in the brain. Heat itself works detrimental to performance, understandable given that the brain is protected by the skull which makes it more difficult to dissipate heat.

On the other hand, not ingesting glucose will reduce blood levels of glucose which also result in reduced glucose delivery to the brain. It is clear from our long and extensive sports research history that glucose ingestion is the more sustainable approach.

Yet make no mistake, trying to dissect the contribution of hypoglycemia from exercise-induced fatigue they found that although low systemic glucose lowers brain glycogen, levels are lowered more due to exercise in the cortex, hippocampus, and brainstem.

“Exhaustive endurance exercise activates brain glycogen breakdown and lactate production more than insulin-induced hypoglycemia” https://journals.physiology.org/doi/abs/10.1152/ajpregu.00119.2020?journalCode=ajpregu

Strategies

Keep in mind the above pieces of information. Not only does the brain generate and consume lactate from its own glycogen stores, on top it also consumes lactate from the circulation.

This is in balance with the movement force generated. Higher efforts generate more lactate, that lactate is used by the brain to support stimulation of higher efforts. But note that the brain is first so it always consumes more energy before it obtains more energy resulting in lowering glycogen levels over time.

This indicates that even if the circulation provides lactate, it will not be sufficient to sustain the activity for ever.

Glucose is constant and total brain lactate availability(from circulation and endogenous production) drops over time leading to energy shortage for electrical impulses. What can we do to delay this onset in shortage?

Perhaps first we need to understand why lactate is used. It is already evident from the above information but testing on brain slices and particularly the hippocampus where we see the most glycogen depletion, provisioning lactate can induce activity for hours. Again proving that lactate is used for ATP to induce the electrical signals towards the muscle.

“Brain lactate metabolism: the discoveries and the controversies” https://journals.sagepub.com/doi/10.1038/jcbfm.2011.175“Lactate-supported synaptic function in the rat hippocampal slice preparation” https://www.science.org/doi/10.1126/science.3375817

Ketones

There isn’t much choice for the brain for alternative energy sources. Let’s have a look at one known alternative to glucose. Could β-hydroxybutyrate (BHB) also replace lactate while not increasing heat production?

The evidence is very thin so allow me to use research on animals and conditions which we would normally ignore.

Causing ischemia in rats followed immediately with BHB infusion was able to keep ATP production at level together with low lactate production.

“Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats” https://www.sciencedirect.com/science/article/pii/S0021519819302872?via%3Dihub

In fetal sheep, arterial infusion of BHB caused a reduction in glucose usage and an increase in lactate. This test however showed that there was no significant uptake of BHB while at the same time they noted a reduction in glucose uptake. So BHB signaled to reduce glucose utilization yet did not seem to be utilized. This must have meant a reduction in ATP production capability and as expected it resulted in higher lactate production. It is possible that a fetal brain may not yet have the necessary expression for ketolysis.

“Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep” https://pubmed.ncbi.nlm.nih.gov/2100739/

In humans fasting for several days, we see an interesting observation where the authors speculate that the rise in brain BHB helps save lactate (replacing lactate oxidation) in order to explain the paralleled rise in lactate they observed.

“Human Brain β-Hydroxybutyrate and Lactate Increase in Fasting-Induced Ketosis” https://journals.sagepub.com/doi/10.1097/00004647-200010000-00012

What about the heat? Extra heat is created by electron loss from the electron transport chain (ETC). The following paper indicates that BHB works protective.

Conversely, a beneficial influence over the electron transport chain’s redox potential is a mechanism commonly linked to d-βOHB. While all three ketone bodies (d/l-βOHB and AcAc) reduced neuronal cell death and ROS accumulation triggered by chemical inhibition of glycolysis, only d-βOHB and AcAc prevented neuronal ATP decline. Conversely, in a hypoglycemic in vivo model, (d or l)-βOHB, but not AcAc prevented hippocampal lipid peroxidation (Haces et al., 2008Maalouf et al., 2007Marosi et al., 2016Murphy, 2009Tieu et al., 2003). In vivo studies of mice fed a ketogenic diet (87% kcal fat and 13% protein) exhibited neuroanatomical variation of antioxidant capacity (Ziegler et al., 2003), where the most profound changes were observed in hippocampus, with increase glutathione peroxidase and total antioxidant capacities.

source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(16)30655-6

Note the distinction in d and l form of BHB. Some exogenous ketone products contain a racemic, which means both d and l forms of BHB. If you ever consider exogenous ketones then keep in mind that the l form does not help the brain cell to produce ATP.

Finally

It looks like BHB will be supportive of the goal. Serving as a source of energy that replaces both glucose and lactate consumption in the brain without deleterious effects from heat production.

Theory versus practice

But does it work? The theory supports it but trials don’t. Unless those trials lack a proper setup. We have seen a few elements that are important and I’ll add a few more:

  • Does the brain have sufficient ketolysis capacity?
  • Is the exogenous ketone a mix of d and l or just d or just l?
  • How strong is the inhibitory effect of BHB on glucose usage?
  • Is the pressure on pH detrimental?

The following trial used athletes habitually on a high-carb diet. Through a ketone ester they got the BHB up to 3.5mmol (KE) and 4.5mmol (KE+bicarbonate). Urinary analysis showed a 0.03g excretion. This would equal 0.29mmol. Given the 3~4mmol/L this is neglectable.

They did note both a glucose and lactate lowering effect. The following overview summarizes the result.

Although they stated impaired performance due to the on average lower power output, it is important to look at the individual results. There is not a general decrement in performance but very much dependent on the individuals.

As indicated, the pH may be an important factor. We see that the time to exhaustion is improved when the KE is combined with bicarbonate and the response at individual level is much more in agreement. In the picture below you see the KE in the dotted lines, solid circles is with bicarbonate.

“Exogenous Ketosis Impairs 30-min Time-Trial Performance Independent of Bicarbonate Supplementation” https://journals.lww.com/acsm-msse/Fulltext/2021/05000/Exogenous_Ketosis_Impairs_30_min_Time_Trial.21.aspx

What the trial didn’t look at is insulin and circulating fatty acids. The ingestion of the KE could also elicit a sufficiently high insulin response so that the control group would be favored by being able to release more glucose and fatty acids.

MCT oil

Whether there is an advantage or not will depend on optimal conditions.

Again not ideal circumstances but just to show that a difference can be made, the following trial compared MCT versus LCT ingestion on performance. MCT can easily get into the mitochondria to fuel performance and in the liver that means it can be converted to BHB easily so we end up with a more ideal approach rather than an KE ingestion.

Also here we see a reduction in lactate but now the time to exhaustion is stretched to 10 minutes more compared to the LCT group for an intensity at 80% VO2Max. Sadly the comparison is not against carbohydrate ingestion so is the LCT detrimental or MCT beneficial?

“Effect of Ingestion of Medium-Chain Triacylglycerols on Moderate- and High-Intensity Exercise in Recreational Athletes” https://www.jstage.jst.go.jp/article/jnsv/55/2/55_2_120/_article

One last study, in rats, that I want to bring is where they used MCT oil and tested performance in high temperature. An impressive >2-fold increase in endurance. My bet is that the resulting BHB supported this effort but unfortunately they did not measure BHB.

“Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism” https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191182

To naturally raise BHB levels in the blood during exercise, MCT oil ingestion during the activity will be essential. I do not recommend ketone ingestion unless you are a professional well funded athlete because these supplements are expensive.

Although one needs to be careful with acidosis, it could be worthwhile to see where the optimal balance is for the best mix of glucose, BHB and lactate in the blood. Glucose metabolism results in CO2 production so you end up with several acidic components in the body. The answer doesn’t seem to be in exogenous ketones.

A small amount of glucose could help either glucose breakdown resulting in lactate and/or glucose metabolism in the mitochondria to increase the TCA and therefor fatty acid metabolism but it may not even be necessary.

Go out and give it a try and let me know if it works for you!

Pro-tip: The action potential that is required to create the electric impulse towards the muscle depends on a hydrated state of the brain. Reading up on Angela Stanton’s book Fighting migraine epidemic it shows the importance of of hydration to maintain ATP production. In my own experience, having a bowl of soup with sufficient salt before my tougher bicycle rides seems to have good influence. Try it out for yourself!

– – – T H E – E N D – – –

Go vegan, save the animals???

From the moment humanity developed agriculture, it allowed populations to expand but it wasn’t until the industrial evolution that our population saw an explosive growth. The extraction of energy was a turning point but it was only possible to sustain that population if humans managed to secure the equally explosive demand for food.

Obviously humans relied on all possible sources to accomplish this. Both increasing animal sourced food and plant sourced food. Animals are slow to grow and expensive while plants provide many more seeds for offspring and under optimal conditions can even yield multiple harvesting from the same land within the same year.

Protein yield from corn is about 720kg/ha. Yet plant protein is about 80% in bioavailability compared to animal protein. So let’s correct the 720kg to 576kg.

A cow yields a conservative 500 pounds of usable meat. About 227kg of which protein 59kg (~26%). This means we roughly need 10 cows per hectare while a general rule of thumb says about 1.37 cows per hectare (1.8 acre per cow). Thus +/- 81kg/ha.

You can argue about the correctness of those numbers but the discrepancy is so big, it is not worth getting to more precise values. It is obvious with those numbers that people tend to think we should let go of an animal based lifestyle and switch to a plant based one.

However, this would be a very one sighted look at the whole situation. We need to consider other factors. Although those other factors will not change the yield comparison, they may help us think different on the actions that should be taken.

Ruminants do not deplete the soil and create a sustainable land source. They do not require pesticides, gmo, herbicides etc. Generally they keep natural water flow in place, and are a net sink for CO2.

Whether you are a global warming denier or believer, fact is that humans increase CO2 and methane output into the atmosphere. Rice cultivation puts methane (1) into the air. Cultivation started around 5000 years ago and has seen an ever increasing volume. Needles to say, to continue increasing the volume, land has to be taken away continuously from wild life.

Source: http://www.fao.org/faostat/en/#data/QC/visualize

Our need for arable land increases. We are being inventive and reduce the need for land per person but our population keeps on growing. The following chart shows how much arable land there is available per person. It is decreasing.

source: https://data.worldbank.org/indicator/AG.LND.ARBL.HA.PC?end=2016&start=1961&view=chart

Crops protection

Europe is aware of the issue that crops cultivation brings. Pesticides and other toxic products are sprayed on the plants to improve yields but they are a threat for the surrounding animals.

However, driven mainly by human activities, species are currently being lost 100 to 1,000 times faster than the natural rate; in the EU, only 17% of habitats and species and 11% of key ecosystems protected under EU legislation are in a favourable state.

Those products are not used for livestock.

If we move away from reliance on animals as our food, we will eventually cause them extinct. This is already happening now as we want to protect our food from wild animals and take up their space. By not relying on food from domesticated animals, we can and will get rid of them by taking up the land they are now occupying.

We try different things like creating urban agriculture but this is done in the most expensive housing places. This approach is just another proof that we are pressed for available land.

We already started experimenting with this for our astronauts and now we moved to creating plant-based burgers, imitating meat.

This is the future we are moving to if our population keeps expanding and there is no sign of this changing.

Do we have a choice really? Probably not. Is it an issue? That depends on our level of knowledge. We all want to live and we want to live healthily. Whatever diet or solution you prefer, we are not there yet. Our population is sicker than ever because we don’t know how to proactively generate health. We are good at keeping you alive but not in a healthy way, not by fixing the root cause and restoring good health.

But perhaps our population question gets resolved by itself? https://www.renalandurologynews.com/home/news/urology/reproductive-medicine/vegetarian-diet-lowers-sperm-quality/

Soil fertility

Another point to consider is how are we going to maintain soil fertility? We may be improving our techniques but at the same time face problems giving plants the necessary nutrients.

Source: https://www.globalagriculture.org/report-topics/soil-fertility-and-erosion.html

Without proper manure, the soils get more and more depleted loosing their yield.

Is it all bad?

Slowing population growth

Maybe not. If we can keep increasing the mean age, it seems we automatically cap our offspring. Looking at our world population there is a decline in the yearly percentage increase (3). Yet there is still a growing trend. This seems to be in line with the increase in mean age which is visualized in the following chart.

Source: https://ourworldindata.org/age-structure

Yield improvement

We are also getting more efficient. At least in case of cereal we are able to increase the yield per square meter of land used and have been quite good at it as shown by the following graph. Note however that this cannot be stretched forever and more importantly, despite the higher efficiency this graph does not show us if we are using more land or not for cereal production.

source: https://ourworldindata.org/crop-yields

Further improvements can be obtained in the way we cultivate rice. Reducing the flooding gives better yield, lowers water consumption and reduces methane output (2).

Indoor farming

Perhaps a very interesting development and certainly needed, is the indoor farming. If we get this right we can create arable land while not taking away land. But we’ll have to get this right in terms of nutritional quality, energy efficiency etc in order to succeed.

But in how far is this just delaying the inevitable? Where is that drive for efficiency coming from? Isn’t it because obtaining land becomes increasingly more difficult? We try to preserve nature but how good are we succeeding at this?

Animals under extinction

Have a look at the WWF list of animals under threat. These are all wild animals. We continue to take up their land to create new arable land, further supporting our expanding population, further requiring arable land.

The guardian reported on a study looking at exactly this topic.

Some 5,407 species (62%) were threatened by agriculture alone.

Lifestock

We are also taking up land for livestock so it is not just all about plants but there are more sustainable practices emerging such as regenerative agriculture. Thanks to the use of livestock we are actually able to prevent desertification. This means making useless land useful again. This is today not possible with our techniques, we need the livestock for that.

Finally

The point is, whatever makes our population more sustainable will cause further extinction of animals. So what I want to say is, if you think going vegan or vegetarian is going to save the animals, give it a bit more thought. You’ll be contributing to their extinction rather than protecting them. It’s an illusion.

The arguments back and forth on food yield, health, climate etc all don’t matter. The fact that this is being argued, shows we are getting squeezed on resources due to our population. No matter what diet we follow, we can’t solve the problem with a growing population.

Put your brain power into how we can sustain a smaller smarter population that prospers technological advances and spares what is left of nature and who knows even let nature blossom again. Maybe we should start with putting a fence around ourselves to protect nature from us rather than putting animals behind fences to protect us?

Whatever we do, however we solve it, it will have to be in a way that brings us excellent health. Health and longevity together with technological advances are the elements that reduce our population in a natural way. One thing is for sure, we need nature for our mental health. And wild animals are part of that nature and part of the effect on our mental health.

References

(1) “Methane Emissions from Rice Cultivation: Flooded Rice Fields” https://www.ipcc-nggip.iges.or.jp/public/gl/guidelin/ch4ref5.pdf

(2) “More Rice, Less Methane” https://www.wri.org/blog/2014/12/more-rice-less-methane

(3) https://www.worldometers.info/world-population/world-population-by-year/

Freeing the brain

I have been interested in the brain for a while, its capacities, functioning, its role within the body. Youtube at some point presented me some videos about psilocybin. After some more information, checking safety and addiction, it seemed safe and non-addictive so I gave it a try. The first time amazed me so I gave it a second try one year later.

What you will read below is the experience and insights it has brought me. It was so profound that I had to write it down and share. You will read how I finally understand how the brain functions, creating awareness and our “self”.

The sensations and thought process (observe and understand)

As it was my second time, I understood the signals. A sense of sleepiness starts to come up. I knew I will want to close my eyes so off to bed and let it happen.

Things start to change, I start to feel cold although I’m in bed covered and with a sweater. The feeling of the body starts to disappear, it returns when I think of my hand for example but attention goes away completely. Sometimes there is a pulse of warmth behind my ears. A welcome warmth because I feel cold. Not a constant pulsing, not in line with my heartbeat.. Where is my heartbeat? it is so weak I can hardly feel it.

It is as if my body is slipping away. Then a sensation comes like a sound in the distance that rapidly approaches getting louder and at its loudest I snap my eyes open and it is gone. It felt like a life surveillance, a life pulse running through my body making sure life remains.

Then I realized it is my own brain scanning the body to make sure it keeps functioning. The brain is in control and it depends on the body to survive.

I started to get strange imaging, shattered, mixed. Constantly switching between 2 images, back and forth. What is that?

I start to realize, the brain needs to observe itself. This is strange, the brain created an observer that monitors itself. But the brain is itself and the observer. I start to understand, the brain created cognition to be aware but it also needs to evaluate itself, observe that everything is OK. It needs to check that the lungs are still functioning to bring in oxygen.

The observer has the role to interact with the surrounding. It controls external stimulation to protect the core but it also controls the core to so that it behaves properly with the external world.

It isn’t really an observer, more like an agent. Agents monitor and regulate. It is an active state. A lot of energy goes into this active state. Energy is important.

The brain is very powerful. If it gets distracted, if it doesn’t monitor then it risks dying. It must monitor the body. It is so powerful and complex. This reasoning requires energy. That is why I feel cold, don’t move and in this dream state. My brain has set the energy consumption of the body to the minimum. As much as possible is going to the brain.

The brain is trapped in a body and depends on it for its survival. It must monitor the body. This is why cognition exists. To extend the brain with the body and care for the body. What stops us from eating our own arm? The brain has to be aware that this is an extension of itself. Awareness.

This is why self-awareness, cognition, exists. An understanding of the body by the brain and how to use it for its own survival.

I start to understand multiple personalities. self-awareness, personality is a creation of the brain. It also had to create this observing cognition, it also created the agent cognition. Are we really one person? One brain yes, but multiple persons, working coherently together. They are not persons, the are more like functions each with their role to play in the totality.

The brain needs a stable core, the main cognition, for survival thinking and decision making. The other functions are supportive to keep the core stable. The core needs to reason and gain insights. This is a fundamental property, this is what learning is about and how the brain builds on what has been learned.

Processing requires reasoning and gaining insights. In an active state this cannot be done. Energy either goes to the active state or to this processing. That is why we dream, to minimize the active state so that we can process events, impressions. Reasoning about it to understand the meaning, how to deal with it. Knowing how to deal with it requires gaining insights. This is why we reason.

I’m starting to understand the brain, I’m starting to understand my “self”. The brain is a collection of cells, it is in a master-slave relation with the body in order to keep itself alive. The master is depend on the slave. The brain can be a danger to itself if it doesn’t monitor and take care of the body.

I understand now what the purpose of dreaming is. Processing these events, impressions or they will influence the core cognition, distracting it, no longer making optimal decisions.

The brain is complex. It is fascinating how I can observe myself and at the same time be myself. I realize observing is an active state, that too draws energy.

This whole session was a constant flux between observing myself and being myself. I had to observe myself, my thoughts, my body to learn about myself, the brain mass, how it functions.

All these thoughts and observations.. what I was doing was reasoning and gaining insights.

Am I right about all this? Absolutely. Why? Because these are my thoughts and my insights. They are right for me and that is what counts. We all need to create our own insights and they are true because they are ours.

When all is processed, our core cognition is stable. It is centered and doesn’t get distracted easily. This is when you are calm, serene, relax. This is where you are “OK” and can truly express everything is “fine”. No anxiety, no aggressiveness, no happiness.

No happiness? Happiness is not a balanced state. It is an escape from negativity, it is a distraction from what is not processed.

The core can experience emotions in different directions but should always return to the center. It cannot afford chronic influence because this core is responsible for survival.

Anxiety, depression, schizophrenia … all these ‘psychiatric’ disorders start to make sense now. They all impact the functioning to have a stable core.

Physical effects

As you get into the dreaming state, you start to feel cold.

What we have below is a view on my hart rate. In yellow you see the decline that started after taking the psilocybin. For comparison, my heart rate during sleep averages at 50 bpm but in this case it went down to 39bpm!

In light blue you see the movement level. As I got to the lowest heart rate, my movement stopped for an hour.

I felt hunger throughout this time and a bit of the hunger noise in my stomach so I got up to eat. It was not easy to walk, a bit like you are drunk. The fine tuned control wasn’t there.

After eating, I went to lay on the sofa and continued again into dreamland, roughly from 4pm to 5pm.

Indicated in magenta is the period across which I could feel it being effective. But even after that the thoughts keep on running.

I have written about how energy is regulated via the hypothalamus. It turns out that psilocybin reduces blood flow to the hypothalamus which explains why I got cold, reduced heart rate and felt hunger. When the hypothalamus perceives low energy, in this case caused by the reduction in blood flow, it regulates the body to reduce energy consumption, free stored energy and stimulate energy intake (hunger).

https://www.imperial.ac.uk/news/106668/magic-mushrooms-effects-illuminated-brain-imaging/

Cooking

The cooking though made me realize what our brains are capable of when they are able to fully use the energy. I cooked chopped up bacon and eggs. I always like the egg yolk to remain complete and running but I never succeed in that.

First the bacon, I was staring at the fat and somehow I was able to see the color of the bacon at the bottom via the color of the fat. When I flipped the bacon, it had exactly the color that I was seeing. Is it an illusion or was I able to know somehow?

Now for the egg yolk.. I moved around the bacon and egg white with a fork (!) Moving around flipping bacon and egg white without touching, without moving the egg yolk. The end result was perfect. Nicely colored bacon, egg white fully cooked and egg yolk complete and still liquid. I never succeeded, perhaps never bothered to try? But I did it this time, the focus was so intense.

What I learned from all this learning

The brain in a box

Physically, the brain, a group of cells, cannot see. It cannot feel nor hear. It does receive electrical impulses, stimulation generated via the nerves. This is problematic because how do you know what all these impulses mean? How do you know the difference between an impulse that means a difference in temperature versus an impulse that means someone touches you?

That question is already wrong, “touching you”? You, the brain isn’t being touched, it’s the body in which you sit as a brain.

The brain had to evolve to generate cognition, a way to create self-awareness, a way to understand that the body in which it is sitting forms one complete part with itself, under its control.

Like a robot that is switched on and discovers that it has arms and legs and that it can control these parts. The brain has to consider this body as part of its “self” in order to understand that it needs to take care of this body.

The brain needs to use this body to survive. It needs to control the body in order to stay alive. Obtain food for both the brain and the body, breathing, stay away from negative body impact, prevent from being attacked. The brain has to take care of the body for its self-interest in surviving.

This cognition, this self-awareness is a projection of the complete unity of the brain and its body and its surrounding. This cognition is created to consolidate the totality and take decisions to succeed in survival of this unity.

The stable core, centered “self”

Throughout the day, we experience events which leave impressions in our memory. The brain needs to learn from these events, it has to evaluate, it has to reason about it in order to learn what it means and understand. Future evaluation/decisions make use of all these gained insights.

Throughout the day, the brain cannot spend the time and energy doing this. Such a processing is energy intensive so it is done during sleep where movement stops, feeding, visual observation and evaluation etc.. all these activities stop so that the brain can redirect the energy towards this processing.

This processing is crucial. This processing means reasoning about it and gaining insights. Once insights are achieved, the reasoning is no more necessary. If this process cannot take place, if those insights are not generated then these impressions remain active.

Such unprocessed impressions destabilize the cognition. The agent and the observer both are active states and becomes mixed up with these impressions that have not been processed and put aside. When that happens, the decision making to enhance survival becomes endangered.

As an example, a traumatic experience, for example the loss of your child, is hard to process. The enormous amount of grieve, sadness, stress will keep you from being able to process and lead to a state of depression. This influences decision making so that you don’t feel like getting up in the morning, you don’t find anymore joy in life, you don’t feel like eating etc..

The cognition that needs to be stable is no longer stable, it is distracted by such a trauma so that it cannot take the optimal decisions anymore to survive.

Psilocybin is used with success to treat depression. Whatever the cause, they are able to process these impressions, reason about it and gain insights.

For those living in the UK, you can watch a BBC documentary where they followed a trial using psilocybin to treat depression. Otherwise you can also see the documentary here. The documentary is called “The Psychedelic Drug Trial”.

– – – T H E – E N D – – –

Xanthelasma

People may be affected by a fatty deposition in the eyelids. The effect is more easily seen in people who have elevated levels of cholesterol and is therefor sometimes used as a marker of hyperlipidemia.

But I’m not interested in hyperlipidemia although I keep it in mind that lipid deposition is part of the pathology.

My interest is more in finding out what causes it and therefor I went in and try to understand it a bit better in the hope that it may reveal something useful for those who are affected.

Histiocytes

Different sources tell me xanthelasma is caused by histiocytes which develop into a foamy cell. Foamy due to how they look under a microscope.

Xanthelasma (pronounced “zan-the-las-ma”) is a non-cancerous growth made up of immune cells called histiocytes. Histiocytes are specialized cells that help remove waste products from the body. The histiocytes in a xanthelasma look much larger than normal histiocytes because they are full of lipids (fat). Xanthelasmas appear as small, yellow bumps on the upper, and sometimes lower, eyelids. Xanthelasma is a type of xanthoma.

source: https://www.mypathologyreport.ca/xanthelasma/

That is as far as most sites go but this is already quite good. It makes it worthwhile to check out what histiocytes are and why they collect these lipids, presumably LDL cholesterol.

Histiocytes are differentiated monocytes which ultimately come from the bone marrow. Monocytes can also differentiate into macrophages which is interesting as those also can form foam cells as noted in atherosclerosis. So naturally there is a concern that xanthelasma is somewhat predicting CVD.

Histiocytes can further evolve into Langerhans cells which are tissue resident macrophages so you can see they are very closely related.

Here I have broaden a bit the search to see what happens to histiocytes at various locations, not just on the eyelids. Just to see if there is a general tendency to form foamy cells or if that is isolated to the eyelids.

There is surprisingly little literature available. One property of these types of cells is that they exert phagocytosis to take up debris and bacteria. So I looked for the combination of foam cell feature and detection of bacteria. Below are several of the results.

1st case, A bone marrow sample showed that the histiocytes contained the bacteria Brucella Melitensis. A 6-week antibiotics cure for this gram-negative bacteria resolved without recurrence.

https://jamanetwork.com/journals/jamapediatrics/fullarticle/348928

2nd case, A severe case of necrotizing Escherichia coli skin infection marked with foamy histiocytes and gram-negative staining for cocci and rods.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8102677/

3rd case, An other rare infection case but in this case caused by the Actinomyces bacteria. This time there are no foamy histiocytes but there are foamy macrophages. However this is done under a microscope so it is not done through staining.

https://sites.kowsarpub.com/apid/articles/13049.html

4th, Leprosy is caused by the gram-positive Mycobacterium leprae bacteria.

https://dermnetnz.org/topics/leprosy-pathology

5th case, tuberculosis caused by Mycobacterium tuberculosis marked by foamy macrophages.

These cells are filled with droplets of lipids, a well-known nutrient for persistent bacilli. We found that within these cells, the bacilli do not replicate, but remain alive and seem to internalize host lipids. The foamy macrophages might thus constitute a reservoir for persisting bacilli within their human host, and could provide a relevant model for screening of new antimicrobials against non-replicating persistent mycobacteria.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2575403/

6th case, a rare bacteria Stenotrophomonas maltophilia septicemia marked by cutaneous foamy macrophages.

https://pubmed.ncbi.nlm.nih.gov/33034921/

Several cases and some more literature tell me that first of all the distinction between histiocytes and macrophages is very vague and not always determined. Secondly, apart from other possible causes, both histiocytes and macrophages engulf bacteria but do not always seem to get rid of them. Instead, these bacteria succeed in surviving inside the cell so that the foamy histiocyte persists. It is proposed in the link on tuberculosis that the bacteria even drive the uptake of lipids by the cell.

If bacteria sort of direct the host cell to take up lipids then higher circulating lipids may help in succeeding. I suspect the bacteria enforce this through how they affect metabolism of the host cell.

Advice

The conclusion is not bullet proof but it shows us a first hint of what could be going on.

1) There is a chance that you developed Xanthelasma due to an ongoing bacterial infection. You could discuss this with your doctor/dermatologist and ask for a biopsy to test for bacteria. If the bacteria can be identified then they can prescribe the most effective antibiotic for it and hopefully that will resolve the issue.

It is important to match the right antibiotics. There are broad purpose antibiotics available but that could be a hit or complete miss.

2) As an alternative you could try sunbathing, exposing the affected area to direct sunlight. Naturally don’t overdo it from the start as you’ll easily burn your eyelids. By inducing vitamin D production in the affected areas, you give the cells the chance to produce its own antibiotics. This is especially true for skin cells.

Many cell types possess genes that make antimicrobial peptides (AMPS) (endogenous antibiotics), recently discovered to be regulated by vitamin D. Two examples are cathelicidin and beta defensins, both bioactive against many different bacteria, fungi, mycobacteria, parasites and viruses.

source: “The Essential Role of Vitamin D in the Biosynthesis of Endogenous Antimicrobial Peptides May Explain Why Deficiency Increases Mortality Risk in COVID-19 Infections” https://www.preprints.org/manuscript/202005.0265/v1

“The Human β-Defensins (-1, -2, -3, -4) and Cathelicidin LL-37 Induce IL-18 Secretion through p38 and ERK MAPK Activation in Primary Human Keratinocytes” https://www.jimmunol.org/content/175/3/1776

A warning though, these lysozymes are not effective against all bacteria. But it is a cheap convenient treatment if you live in an area blessed with sufficient sun. Perhaps also something worth talking to your dermatologist about. They can offer a treatment with UV light that may stimulate the same vitamin D production.

And another warning, if you plan to do something about it surgically then keep in mind they advise to stay out of sunlight so be sure to discuss this with your doctor.

Good luck, I hope this is able to help you out.

– – – [ T H E ] – [ E N D ] – – –

The misunderstanding of endurance adaptation and how to train all muscle types together

There are plenty of articles that explain much more in detail the different muscle fiber types and how to train for endurance or how to build muscle so I won’t go into those details. What I do want to address is the issue with getting both trained at the same time.

First, the problem with muscle fiber types and training type

The main difference between type I and type II is in the way they generate power and for how long they can do this. Type I is low in fiber growth but dense in mitochondria. Its strength comes from longer sustaining ATP production. This makes them very well suited for endurance. Type II is the opposite, it responds easier with growth but is lower in mitochondria. Because it can grow larger in size more easier, its strength comes from the total capacity of the fiber contraction. Although it has fast ATP production, this is limited in time because the production capacity is limited.

They are essentially each others opposite:

Muscles are a mix of both fiber types. In some muscles, the mix will dominate towards type I while in others it is more balanced or goes towards type II predominantly. And then there is of course your genetics which may shift the balance further towards one or the other.

In a simplified way, this result in the following situation:

So what is the problem?

1) One type of exercise trains one type of fiber.

In order for the fiber type to adapt to a training stimulus, the muscle cell must run out of energy. Type II responds to weight lifting because the heavy weight is carried by type II. They can generate the power to lift the weight (assisted by type I) but once they are fatigued and have reached the stimulus, you cannot lift anymore. But the type I fiber didn’t reach fatigue yet, it is just not strong enough to continue by itself with the same weight.

Endurance training on the other hand is relying on type I fiber and then we have on top of that the complexity of type IIa fiber which can shift its profile between the two extremes depending on the type of training you do.

2) Endurance training inhibits mTOR (muscle growth)

The following is an often visualized picture of training adaptation:

It shows how endurance activates AMPK and that cascades down to blocking mTOR which runs the protein synthesis. Although this is correct, I’ll show why this is also wrong and leads to misunderstanding.

Mitochondrial biogenesis

In order to explain what is wrong with that picture, we need to understand what creates more mitochondrial mass. This is where the increase in strength is coming from for endurance.

PGC-1α is the factor that opens up the transcription of the genes for mitochondrial protein production. AMPK phosphorylation (activation) induces PGC-1α and this AMPK activation in turn is driven by low levels of ATP.

This paper shows that by inhibition of nitric oxide, the activation of PGC-1α fails by AMPK alone.

“Nitric oxide and AMPK cooperatively regulate PGC-1α in skeletal muscle cells” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2988518/

Although not entirely comparable to skeletal muscle, the heart muscle type, which is the most important endurance muscle, shows us that insulin is involved in mitochondrial fusion, to make them bigger and produce more ATP.

But a study in humans looking at skeletal muscle also showed that insulin itself can stimulate mitochondrial biogenesis. These results were obtained together with leucine infusion to maintain plasma levels.

“Insulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 Signaling Pathway” https://diabetes.diabetesjournals.org/content/63/1/75“Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC164701/

Putting both together, it is critical to understand that nitric oxide production is stimulated by insulin. This is important for insulin to get across from the blood circulation into the muscle cells.

“Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179)” https://pubmed.ncbi.nlm.nih.gov/11402048/ – “Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release” https://pubmed.ncbi.nlm.nih.gov/8083357/“Nitric oxide release accounts for insulin’s vascular effects in humans” https://pubmed.ncbi.nlm.nih.gov/7989610/

“Nitric Oxide Directly Promotes Vascular Endothelial Insulin Transport” https://diabetes.diabetesjournals.org/content/62/12/4030

What stimulates insulin release? Leucine in your food (or protein shake) triggers the release of insulin from the pancreatic beta cells.

“Leucine metabolism in regulation of insulin secretion from pancreatic beta cells” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2969169/

So, AMPK inhibits mTOR but this is only until food comes in that allows the cell to adapt and build the necessary protein to become more resistant. This food will activate mTOR. AMPK will split (fission) the existing mitochondria and influences the type of protein that are produced so that when mitochondrial protein are produced, they are assembled into those fragments created by AMPK.

Blood Flow Restriction (BFR)

BFR is special because by its reduction in oxygen availability, it affects all fiber types at the same time. The reason is that hypoxia will limit the ATP production in mitochondria so that the glycogen will become the main source of ATP production via glycolysis instead of glucose or fat via the mitochondria.

Type II fibers already have reduced mitochondria so they are already more prone to glycolysis. Type I fibers are more resistant so they may still require a bit more prolonged exposure to BFR.

Below is a schematic of how BFR will trigger training in both fiber types, covering the info provided above.

So go and lift your weights but apply BFR to stimulate endurance adaptation simultaneously in your type I fiber while also enhancing the effect on type II fiber if that is what you are after.

When you go running, cycling.. apply BFR so that it enhances the endurance training effect and stimulates muscle growth in those type II fibers.

Feeding

In order to adapt to the training stimulus, new protein must be build. The fiber type will determine how the response is made. Type I will push for mitochondrial protein to increase endurance capacity while type II will push for muscle protein synthesis in order to grow new muscle cells aka proliferation aka hyperplasia.

As discussed above, insulin alone will not do the job, it needs to be combined with sufficient leucine so make sure to have a protein source that contains enough leucine.

AMPK, via PGC-1a activates the transcription to build mitochondrial protein which are assembled by mTOR. This is why type I muscle fiber do not grow in size so easily. It first inhibits mTOR and then changes the program to make sure that, when mTOR gets activated again, it concentrates on mitochondrial protein construction instead of muscle protein.

Metformin

Just as an example to show the effect. Because metformin stimulates AMPK it was thought that it would result in a benefit for endurance adaptation. Rather the opposite is true and it blunts the adaptation. Although this was not tested yet in the literature, to my knowledge, I suspect that the chronic stimulation of AMPK also causes a chronic downregulation of mTOR which could explain why there is no buildup of mitochondria and thereby lack of increased endurance.

“Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK” https://www.cell.com/cell-reports/fulltext/S2211-1247(19)31267-7

“Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults” https://pubmed.ncbi.nlm.nih.gov/30548390/

Probably the reason why they thought it would enhance exercise is because they made the same mistake as I did and didn’t understand that the mTOR inhibition needs to be lifted in order to build those mitochondrial protein.

You actually need mTOR for mitochondrial protein synthesis just as much as any other protein synthesis.

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The bigger picture on fat-adaptation

A paradigm shift in understanding

I’ve looked into various topics related to metabolism and what a high fat diet changes versus high carb. Topics such as heat production, weight management, ATP production, protein sparing, lactate, BHB, glycogen, starvation, evolution, bone health and collagen cross-links specifically, pyruvate etc.. have come together in a meaningful way.

What is presented below is a paradigm shift in my understanding of why the things are the way they are and at the center we find the evolutionary implementation of heat production.

When we acquired the trait I don’t know, but we certainly do posses the ability to increase our body heat production. It is possible this is a feature that developed when the first forms of multicellular life was challenged by snowball earth or maybe it came in later.

Heat production to survive cold is, needless to say, essential.  I’ve already argued before (see references at the bottom) that the main purpose of body fat isn’t primarily to survive starvation in winter periods.  It does help of course but it doesn’t work in cold climates.  Do not eat for a few days and your body heat drops noticeably.  Cold can kill you overnight with hands and feet the first to freeze.  Not ideal to survive.

So what does it take to increase heat production? What are the consequences?

Chronic higher fat availability (circulating in our body) seems to be required to sustain a higher heat production capacity.

  • Your body needs sufficient access to fat, continuously.

On a per gram basis, because fat has 9 calories, it can produce double the amount of heat.

Using fat for heat production poses two problems though:

  1. Producing more heat is an extra energy consumer
  2. Chemically an increase in heat can cause more undesired reactions

1) If heat production is so important for survival then it requires serious energy optimization to cover the timeframe of cold exposure.  This can be done by lowering ATP requirements. 

This is actually being done. When the body shifts energy metabolism almost fully to fatty acids, ATP production is reduced where possible. The brain is exempt from this as it has a very limited supply of fatty acids that it can work with.

Brown fat, which is the source of the increase in heat production, becomes very active yet does not produce a lot of ATP because the energy is being wasted towards heat.

When a cell reduces its ATP production to save energy for heat production, it has to inhibit growth.  We see that AMPK inhibits mTOR, mTOR doesn’t inhibit AMPK! This naturally reduces the amino acid requirements.

2) But why fat?  Why not also use glucose to lose some electrons and generate heat?  Why did evolution decide on fat?

The greater energy density per gram is already a major advantage but when the heat is increased, using glucose becomes increasingly a problem due to glycation (the Maillard reaction).

Glucose binds to protein and fatty acids. This renders protein unusable and together with the modified lipids it creates advanced glycation end products (AGEs).

Chemically it seems necessary to reduce circulating glucose in our bodies. Damaged protein would require building new ones but we’re in a situation where we cannot spend ATP on it.

Evolution seems to have sorted out this situation long time ago. If heat needs to be produced:

  • circulating glucose must go down
  • fat must be used for heat production

This is why we also see a reduction in pyruvate. It means that less amino acids are used for glucose production while favoring glycerol. This way glucose availability remains low and we can avoid protein breakdown.

The lower we can keep glucose, the more heat we can generate but this has put evolution in front of an other problem to solve.

2 problems solved, 1 created

With ATP production reduced and glucose levels suppressed, the cells within the body risk falling short on ATP. A monitoring and signaling system is required and so evolution evolved providing a solution.

This is where cytosolic glycogen comes in.  When cellular glycogen levels decline, more cytosolic glycolysis takes place generating more lactate.  This increases BHB influx into the cell to support ATP production. 

Cellular glycogen works as a measurement of sufficient ATP production.  Sufficient extracellular substrate maintains glycogen levels, insufficient makes them decline. This is also why hypoxia directly stimulates lactate production. It immediately threatens mitochondrial ATP production.

Increased lactate will also stimulate more mitochondrial biogenesis so that more ATP can be produced through oxidation in the mitochondria rather than cytosolic glycolysis. 

Mitochondria therefor not exist to maximize ATP production, rather they exist to support a minimal level of mitochondrial ATP production.

In summary

  • To produce extra heat the body must divert the energy from growth towards heat production.
  • This can only be done if damage to protein (and lipids) is reduced
  • Damage can be minimized when glucose is reduced
  • Reducing glucose makes fat the only viable choice
  • Low ATP is risky so a fail-safe mechanism is developed with beta-hydroxybutyrate as the fuel to resolve low availability

Related publications

—- T H E – E N D —-

Bone health on a ketogenic diet

Pulling the final plug on attacks

Attacks? I follow up on all published papers related to ketogenesis and although the execution may be done correctly and data may be generated correctly.. the circumstances are often specific and the conclusions are stretched beyond the scope of what the data is representing or can represent. All to fulfill the personal bias.

“A Short-Term Ketogenic Diet Impairs Markers of Bone Health in Response to Exercise” https://www.frontiersin.org/articles/10.3389/fendo.2019.00880/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE

Why? The ketogenic diet is the very opposite of what is generally recommended as the ideal diet. High in (animal sourced) fat, for sure leaving out seed oils, sufficient protein and drastically limiting carb intake. This goes against what nutritionists have learned and recommend and similarly for anyone in the medical field. It is completely opposite to the ideology of other diets such as veganism.

So you can imagine it generates skepticism and enemies from different areas. Apart from clashing with personal conviction, it also threatens a whole carb-centric industry and a pharma industry that relies on managing disease rather than handing the root cause and curing disease.

Since I got interested in the ketogenic diet and metabolism in general, I have found nothing left of the original negative claims and ‘dangers’ following a ketogenic diet (KD) except for impaired performance at very high intensities such as in endurance racing although I have a theory on how to fix that.

One last element on the list is bone health. This keeps on being a topic that comes up regularly and with this post I want to dig in deeper to understand what bone health means and what can we expect from a KD.

A first signal that made me question current dogma was when looking at pro cyclists versus amateurs. The pro cyclists had lower bone mineral density (BMD) and lower bone mineral content (BMC), both considered markers of bone health.

“Professional cyclists have lower levels of bone markers than amateurs. Is there a risk of osteoporosis in cyclist?” https://www.sciencedirect.com/science/article/abs/pii/S8756328221002672?via%3Dihub

Pro’s spend a lot more time sitting on their bike and generally are one of the most lean athletes so low weight. When we look at the elite of the elite, Tour de France contestants, then we don’t see the types of fractures (clavicle, wrist, hand, femure) represented by the location where low BMD is found (femoral neck, total hip, lumbar spine).

“Prevalence and Epidemiology of Injuries Among Elite Cyclists in the Tour de France” https://pubmed.ncbi.nlm.nih.gov/30202769/A Systematic Review of Bone Health in Cyclists” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3230645/

These guys crash at high speeds, off cliffs, against walls etc.. Perhaps we think we understand bone health but do we really?

Understanding bone health

Most people do not think about bones as a dynamic thing but constant remodeling is taking place. Remodeling is taken care of by osteoclasts which break down old and damaged bone while new bone is formed by osteoblasts. A proper balance needs to be maintained between both to support healthy bone and adaptive towards increasing resistance to higher forces such as from resistance exercise and stronger muscle.

Remodeling itself may need to be flexible, increasing when needed and reducing when not required as much.

In studies we find tartrate‑resistant acid phosphatase (TRAP) and collagen degradation via C-terminal telopeptide (CTX) used as a marker of bone resorption while alkaline phosphatase (ALP) and procollagen 1 N-terminal propeptide (P1NP) as a marker of bone formation.

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“Disorders of Bone Remodeling” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3571087/

Often we can look at studies that investigated and found causes of increased fractures such as the next one looking at Type 2 Diabetes (T2D). Due to lower levels of osteocalcin (vitamin K and D deficiency) and bone remodeling, patients have normal BMD but increased risk of fracture. They specifically point out the bad damaged structure rather than BMD as a cause of the higher risk.

According to the article, osteoblasts/osteocytes are impacted in viability and reduces dendrite connectivity through high reactive oxygen species (ROS) when metabolizing glucose. They need a high anti-oxidant defense which is brought up by increased fat metabolism through glutathione.

The following chart is complex but their argument is that decreased bone health is driven by hyperinsulinemia. A KD keeps your insulin very low. One of the results of a higher reliance on carbs is that there are more advanced glycation end products (AGEs) formed. They end up creating cross-links between the collagen, just like the CTX, making the bones more stiff.

“Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas” https://www.mdpi.com/2227-9059/9/9/1165

Collagen in the bone is enzymatically cross-linked with each other to provide stiffness. This cross-linking under normal conditions is done by dihydroxylysinonorleucine (DHLNL), hydroxylysinonorleucine (HLNL) and lysinonorleucine (LNL) which are considered the immature links. These substances are easier extracted yet with a lower yield from osteoporotic patients. Over time they further evolve towards mature cross-links pyridinoline (PYD) and deoxypyridinoline (DPD).

The second paper below indicates that especially the immature cross-links are reduced when in competition with AGEs.

Correlations between each of the lysine-derived AGEs (i.e. CML, CEL and pentosidine), and the enzymatic cross-links were analyzed because these AGEs possibly compete with enzymatic crosslinks for formation sites36. The amounts of DHLNL, HLNL, and LNL were negatively correlated with CML, CEL and pentosidine, whereas no such correlation was observed for PYD and DPD (Table 5).

“Reduced concentration of collagen reducible cross links in human trabecular bone with respect to age and osteoporosis” https://pubmed.ncbi.nlm.nih.gov/8922646/ “Mass spectrometric quantitation of AGEs and enzymatic crosslinks in human cancellous bone” https://www.nature.com/articles/s41598-020-75923-8

A further look at T2D confirms the same story. AGEs replace the enzymatic cross-links, increased osteoclast activity and reduction in osteoblast activity.

The aggregation of AGEs causes non-enzymatic cross-linking of collagen, disrupting the adhesion of osteoblasts to the extracellular matrix and resulting in bone fragility [16] (Fig. 3). These alterations of extracellular matrix also reduce alkaline phosphatase (ALP) activity in mature osteoblasts, affecting bone mineralization [16]. The receptor for AGEs (RAGE) is expressed in human bone cells and its stimulation drives the activation of nuclear factor kappa-B (NF-kB) in osteoclasts, increasing the production of cytokines and reactive oxygen species (ROS) [17]. High proinflammatory cytokine and ROS levels trigger osteoclastogenesis and stop osteoblast differentiation [1819].

“Diabetes and Bone Fragility” https://link.springer.com/article/10.1007/s13300-020-00964-1

We can start to doubt if BMD and BMC are good markers of bone health. Bone health lays within the structure but that is not something you can easily measure. DEXA scans give you BMD and BMC but nothing on the integrity.

In line with the effect seen in T2D, we also see how sugar sweetened beverages (SSB) have an inverse association with bone mineral density (BMD).

“Sugar-sweetened beverage consumption and bone health: a systematic review and meta-analysis” https://nutritionj.biomedcentral.com/articles/10.1186/s12937-021-00698-1

To me, this starts to show that BMD and BMC are not quality markers. Looking at a few more studies we find a roughly 50% division for fractures in older adults above and below the WHO determined level for osteoporosis. That makes fracture prediction based on BMD basically a flip-of-a-coin.

“Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study” https://pubmed.ncbi.nlm.nih.gov/14751578/ – “Identification of osteopenic women at high risk of fracture: the OFELY study” https://pubmed.ncbi.nlm.nih.gov/16160738/

Perhaps the combination of these factors, stiffness and lower BMD is something to worry about than either alone?

CTX

CTX exists in different forms. The alpha version, left side on the image below, shows declining levels as we age. Generally everything declines as we age, all for the worse.

“The contribution of collagen crosslinks to bone strength” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3868729/

Is it possible that we see a decline in CTX because AGEs are replacing them and cannot be broken down so easily?

Vitamin K2

Deficiency in vitamin K2 (vK2) is a factor that could also lead to poor bone health. One of the vK2 effects noted in osteoclast is the inhibition of NF-kB. Too much osteoclast activity and you get weaker bones.

“The Dual Role of Vitamin K2 in “Bone-Vascular Crosstalk”: Opposite Effects on Bone Loss and Vascular Calcification” https://www.mdpi.com/2072-6643/13/4/1222

Vitamin D

Vitamin D has an important role in bone formation. The active form of vitamin D is calcitriol (1,25-dihydroxycholecalciferol). Calcitriol is beneficial to bone formation by inhibiting the osteoclasts and promoting the osteoblast activity.

“Association of Anabolic Effect of Calcitriol with Osteoclast-Derived Wnt 10b Secretion” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6164019/

Under chronic high fructose intake the levels are reduced.

“Chronic High Fructose Intake Reduces Serum 1,25 (OH)2D3 Levels in Calcium-Sufficient Rodents” https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093611

Fatty acids

Capric acid also reduces osteoclast activity. But again, it is the balance between osteoclast and osteoblast activity that generates healthy bones.

“A medium-chain fatty acid, capric acid, inhibits RANKL-induced osteoclast differentiation via the suppression of NF-κB signaling and blocks cytoskeletal organization and survival in mature osteoclasts” https://pubmed.ncbi.nlm.nih.gov/25134536/

Different fatty acids have different effects. Here we see octanoic acid and decanoic acid analyzed. Primarily octanoic acid showed a reduction in ALP and increase in TRAP.

“Octanoic acid a major component of widely consumed medium-chain triglyceride ketogenic diet is detrimental to bone” https://www.nature.com/articles/s41598-021-86468-9

Thyroid

In a group of familial longevity they found lower bone turnover markers. Increase in TSH was followed by increase in CTX and P1NP so breakdown and buildup respectively.

“Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH.” https://pubmed.ncbi.nlm.nih.gov/34491903

Acidity

One other acid, induced by diet is uric acid. Fructose intake results directly in increased uric acid. Sugar and high fructose corn syrup are major sources of fructose, both via solid and liquid intake. These are highly avoided on a KD.

“Recent advances in fructose intake and risk of hyperuricemia” https://www.sciencedirect.com/science/article/pii/S0753332220309884

Fructose not only causes increased uric acid, it also impairs calcium absorption via the gut.

“Dietary Fructose Inhibits Intestinal Calcium Absorption and Induces Vitamin D Insufficiency in CKD” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2834550/

This is very important because calcium is not only used for bone formation but also for metabolism. With a reduction from the diet, the bones have to give up more calcium to fulfil the needs in the metabolic processes.

Protein

It is so important that it deserves its own chapter. The impact of low dietary protein is often a cause for the noted reduction in bone health and growth stunting in children.

Animal protein stimulates growth more than plant-based protein in children.

“Dietary Intake of Protein in Early Childhood Is Associated with Growth Trajectories between 1 and 9 Years of Age” https://academic.oup.com/jn/article/146/11/2361/4630467

dietary protein is a key nutrient for bone health across the life span and therefore has a function in the prevention of osteoporosis.9 Protein makes up roughly 50% of the volume of bone and about one-third of its mass.10

“Optimizing Dietary Protein for Lifelong Bone Health” https://journals.lww.com/nutritiontodayonline/fulltext/2019/05000/optimizing_dietary_protein_for_lifelong_bone.5.aspx

It should be no surprise that insufficient protein is detrimental for bone formation.

“Protein intake and bone growth” https://pubmed.ncbi.nlm.nih.gov/11897891/

In the elderly population, if anything, we see a reduction in hip fracture with increasing protein. I’m not so happy with these studies non-RCT studies as possible positive effects can be impaired by negative confounders such as high glucose and fructose intake.

“Protein intake and risk of hip fractures in postmenopausal women and men age 50 and older” https://link.springer.com/article/10.1007%2Fs00198-016-3898-7 – “Does dietary protein reduce hip fracture risk in elders? The Framingham osteoporosis study” https://link.springer.com/article/10.1007%2Fs00198-010-1179-4 – “Risk Factors for Hip Fracture in Older Men: The Osteoporotic Fractures in Men Study (MrOS)” https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.2836 – “The Association Between Protein Intake by Source and Osteoporotic Fracture in Older Men: A Prospective Cohort Study” https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3058

In the following study we see that particularly a vegan diet is associated with increased fracture. A hazard ratio of 2.31 is meaningful. This is of course just association but perhaps the info further down can help to clarify potential reasons.

“Vegetarian and vegan diets and risks of total and site-specific fractures: results from the prospective EPIC-Oxford study” https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01815-3

In a healthy population, increased dietary protein resulted in increased urinary calcium excretion but this was paralleled with an increase in calcium absorption.

“Dietary protein, calcium metabolism, and skeletal homeostasis revisited” https://academic.oup.com/ajcn/article/78/3/584S/4690000?login=true

Fractures

Racing bikes are made of a carbon frame. These are very stiff and very strong but only when the force is applied in the right direction. Parallel to the tube, not sideways. Sideways they don’t bend, they snap like a dry twig. Could the same be the case for our bones?

AGEs

One potential contributor to decreased bone health is pentosidine which is an AGE. We saw before that AGEs form bad quality collagen links, creating stiffer bones.

Pentosidine content in bone tends to increase in an age-dependent manner, and different diseases can accelerate the accumulation of pentosidine. Studies in animal models of type 2 diabetes, type 1 diabetes, low and high turnover chronic kidney disease, and postmenopausal osteoporosis have shown elevated levels of bone pentosidine and altered amounts of enzymatic cross-links (lysyl oxidase [LOX]-dependent cross-links). As these diseases are also associated with higher fracture risk, the hypothesis is that pentosidine contributes to fracture risk.

“Pentosidine as a Biomarker for Poor Bone Quality and Elevated Fracture Risk” https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-7693-7_32

Since glycation is often reported as glucose binding with protein, it is often forgotten that fructose (fructation) has an even bigger effect, up to 10-fold higher!

“Nonenzymatic glycation of bovine serum albumin by fructose (fructation). Comparison with the Maillard reaction initiated by glucose” https://pubmed.ncbi.nlm.nih.gov/2537288/

Not only within the body but also via our diet do we ingest AGEs. This Japanese study looked at common food and drinks. At the bottom end we see milk, coffee and tea but the top shows sugar and fructose containing drinks for the most part.

“Assessment of the Concentrations of Various Advanced Glycation End-Products in Beverages and Foods That Are Commonly Consumed in Japan” https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118652

Such dietary AGEs and endogenously produced ones depend on good filtration capability of the kidneys, which are impaired under metabolic syndrome.

“Studies on Absorption and Elimination of Dietary Maillard Reaction Products” https://nyaspubs.onlinelibrary.wiley.com/doi/abs/10.1196/annals.1333.054

To no surprise, people who suffer from chronic kidney disease have elevated serum AGEs and this is reflected in their bones with increased fracture risk.

Pentosidine was remarkably increased in dialysis patients and inversely correlated with bone-formation rate/bone volume and mineral apposition rate. This study suggests that AGE collagen cross-links strongly associate with disorders of bone metabolism in dialysis patients.

“Nonenzymatic cross-linking pentosidine increase in bone collagen and are associated with disorders of bone mineralization in dialysis patients” https://pubmed.ncbi.nlm.nih.gov/21499867/

The enzymatic cross-links is what we want, not pentosidine. By increasing the enzymatic ones and removing pentosidine, we see in the following study an increase in strength. Both calcium content and these enzymatic cross-links were each independently responsible for increased strength. Also in this study they reaffirm that the cross-links determined stiffness.

“Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with human parathyroid hormone (1-34) for 18 months contribute to improvement of bone strength in ovariectomized monkeys” https://pubmed.ncbi.nlm.nih.gov/20959962/

Impact on a ketogenic diet

A KD avoids carbs and fructose in the diet especially from sugar and high-fructose corn syrup (HFCS) and sugar containing beverages, even ‘natural’ fruit drinks which are also high in carbs.

So a reduction in glucose which forms AGEs, a normal or increased calcium uptake due to lower fructose, lower uric acid due to low fructose and sufficient protein.

The diet generally elevates vitamine D and K2 sources and allows stored vitamine D to be released from adipose as weight is lost.

Not only vK2 can suppress NF-kB but also a ketogenic diet.

“Ketogenic diet attenuates oxidative stress and inflammation after spinal cord injury by activating Nrf2 and suppressing the NF-κB signaling pathways” https://pubmed.ncbi.nlm.nih.gov/29894768/

Following an 8-week KD, women on resistance training had a small significant improvement in BMD compared to the normal diet (0.02 versus 0.00 g/cm2).

“Effects of a low-carbohydrate ketogenic diet on health parameters in resistance-trained women” https://link.springer.com/article/10.1007%2Fs00421-021-04707-3

After 12 weeks on a KD, there were no differences found in BMD.

“Keto-adaptation enhances exercise performance and body composition responses to training in endurance athletes” https://www.metabolismjournal.com/article/S0026-0495(17)30298-6/fulltext

A thorough review of bone remodeling and ketogenic diet has been done before but they somewhat left out the impact of dietary protein. A must-read though to get a better understanding in general. It covers a lot of murine studies. Important is that a KD for these animals usually involves highly restricted protein intake.

“Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7796307/

Following up epileptic children who followed a modified Atkins diet (MAD), less restrictive in protein, they found no impact on bone health. Normal bone mass and growth.

“Prospective study of growth and bone mass in Swedish children treated with the modified Atkins diet” https://pubmed.ncbi.nlm.nih.gov/31085021/

Acidity

A KD is typical because it raises the production of beta-hydroxybutyrate (BHB) which is an acid. You could quickly jump to conclusion that this acid needs to be neutralized by binding to calcium leading to calcium deprivation impacting bone formation.

What we do notice is that the pH is maintained within the required range (7.35 – 7.45). A KD reduces the production of CO2 which is also an acid.

I don’t have data to support the following claim but I think it makes sense. When the diet can supply sufficient calcium then it is likely that the balance is kept to deal with acidity so that the bones are not impacted.

The dietary sources on a ketogenic diet are sufficiently high in calcium and the level of protein intake should support calcium requirements.

Protein

Some people claim that protein intake is responsible for acidity. Proteins are made up of amino acids thus indeed also acidic. But a thorough study measuring urine pH, acid excretion and calcium excretion found no relationship with fractures in a long follow-up study of 5 years, including no change in BMD.

“Low urine pH and acid excretion do not predict bone fractures or the loss of bone mineral density: a prospective cohort study” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2890599/

It even seems that protein help to clear uric acid!

“The uric acid lowering effect of protein-rich diets. Behavior of human uric acid metabolism under reducing diet forms with varied protein content” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2890599/

Studies in mice and rats often involve heavy restriction of protein in the diet. Could that influence the results? This is definitely a confounder.

AGEs

This study concluded a low carbohydrate diet reduced renal AGE formation.

“Low-Carbohydrate Diet Inhibits Different Advanced Glycation End Products in Kidney Depending on Lipid Composition but Causes Adverse Morphological Changes in a Non-Obese Model Mice” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6893679/

Summary

Bone Mineral Density is not an indication of bone health. Bone health and remodeling can be impacted by many factors.

  • Increased force requires more remodeling to create a higher density.
  • When switching from a diet that is detrimental for bone health towards one that is good for bone health may be marked by a temporal increase in breakdown markers, especially CTX.
  • Protein in the diet needs to be sufficient. Restricting it too severe such as in animal studies and often in children treated for epilepsy on a KD, will lead to reduced bone density.
  • Something we see in astronauts is that they lose 1% to 2% of BMD every month. Weight loss reduces the strength requirements so we can expect a little reduction in BMD noticeable via higher breakdown activity.
  • Adequate nutritional status of vK2 and calcitriol are important bone mass forming agonists and together with a KD reduce bone breakdown activity.

“What happens to bones in space?” https://www.asc-csa.gc.ca/eng/astronauts/space-medicine/bones.asp

So when studies report a negative effect on BMD then we need to look at all these effects and evaluate whether we are looking at a desired effect or an impaired situation.

The only objective markers for bone health can be found on incidences of fracture rates.

As long as we don’t see an increase in weight lifters and endurance athletes, who have a higher dependency on quality bones, more easily exposed to bone breaking activities, then all we have is association of incorrectly understood markers of bone dynamics.

Similarly, the elderly population is also at increased risk. If we see no difference on a KD then I would consider it safe and a non-issue.

Attacks

Now that we have a little better understanding, returning back to the first paper. The next picture summarizes their conclusions.

CTX is related to collagen while osteoclasts are directly active in the breakdown process. Yet osteoclasts see a drastic reduction. In the diseased states such as CKD and T2D we saw increased osteoclast activity. We saw higher CTX activity in the young versus old population.

So the KD seems to resemble the young and healthy bone dynamics rather than a detrimental one. A stark contradiction in conclusion while the data remains the same.

For CTX we don’t really see any meaningful difference except right after exercise.

Rather than concluding impaired bone health, I would rather raise questions on the understanding of CTX. Especially when CTX and osteoclasts should be in agreement but here are opposite to each other.

Wikipedia is clear about this:

The CTX test measures for the presence and concentration of a crosslink peptide sequence of type I collagen, found, among other tissues, in bone. This specific peptide sequence relates to bone turnover because it is the portion that is cleaved by osteoclasts during bone resorption, and its serum levels are therefore proportional to osteoclastic activity at the time the blood sample is drawn.

source: https://en.wikipedia.org/wiki/C-terminal_telopeptide

P1NP may be in line with reduced osteoclast assuming you don’t need as much buildup when the breakdown is reduced.

“A Short-Term Ketogenic Diet Impairs Markers of Bone Health in Response to Exercise” https://www.frontiersin.org/articles/10.3389/fendo.2019.00880/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE

Furthermore, the study was done short-term (3-3.5 weeks) while we’ve seen a study of 12 weeks showing no negative effect when just looking at BMD.

In other words, shortsighted conclusions .

Food for thought but fear of impaired bone health on a ketogenic diet is not something I’m concerned about. Until further better quality studies paint a different picture.

—- T H E – E N D —-

The intimate triad glycogen – lactate – beta-hydroxybutyrate

There is a close relationship between glycogen, lactate and beta-hydroxybutyrate (BHB) that I would like to highlight in this post. Although it looks like a simple relationship, it has important implications. There is more to cover but I’ll focus on the acute phase.

The essence

A first scenario, no matter the available fuel type (fat, glucose) in the circulation and at whatever ratio, glycogen contributes to the metabolism. I’m referring here to glycogen in all cell types, not just the liver or skeletal muscle cells. Glycogen in a cell is a buffer and a measure of available energy. When energy demand is higher than the rate at which glycogen can be build up, we get a declining level of glycogen. Very simple.

In such a way it is a measure of energy supply from the circulation. Increasing glycogen means sufficiency in circulation and declining glycogen the opposite. With declining levels at some point the situation becomes critical. How do you change the situation? How can a cell signal that it requires more energy?

As the glycogen level gets depleted..

  1. It first of all reduces the contribution of the glycogen to metabolism.
  2. It increases lactate production

Point 1 seems contradictory, we need energy so why reduce the contribution from an energy source? If the fuel in circulation is inadequate and glycogen level is low, the cell will dial down the activity to match what is available from the circulation to save as much of the remaining glycogen as possible. It simply cannot afford full depletion. It will use the glycogen for point 2 to attract more energy from outside the cell.

A second scenario, very similar to the first case but a different trigger, is hypoxia. When not enough oxygen is available, the mitochondria will be impaired in providing the necessary ATP. This also increases lactate production. It is something we know from cancer cells but is not uniquely attributable to cancer cells.

Common to both scenarios, the cell is in trouble for sufficient ATP production. So how can a cell rescue itself? There are a few tricks to rescue itself.

I suspect lactate increases GLUT1 expression so it can try and increase glucose supply to continue its glycolysis but still, this produces a low level of ATP versus what the mitochondria are capable of (yet faster production method).

Increasing lactate in the cytosol also increases monocarboxylic transporter 1 (MCT1) membrane expression. It does this to get rid of the lactate because it brings down the pH, but by doing so it opens the gates through which BHB can enter the cell.

BHB can get processed in the mitochondria and will generate more ATP while not requiring oxygen. So whatever the cause (low glycogen or hypoxia) it can provide more energy in a situation where there is a shortage in energy.

Once the lactate is out of the cell, we are not finished yet. It has to get into the blood circulation and we need to get BHB from the circulation into the cells. Endothelial cells need to get both substances across using the same transporters.

How this happens is not clear. A cytosolic increase in lactate increases the MCT1 expression but now we are outside of the cells. How do we get the endothelial layer to increase locally its MCT1 expression?

I wonder if this is a potential reason for why red blood cells have no mitochondria. They can only process glucose anaerobically so they are a constant source of lactate in the blood. Perhaps they keep the endothelial cells ready (since birth!) for cases where a local rise in lactate may emerge?

We also see the brain producing an excess amount of lactate making it export lactate at rest. Why wouldn’t it absorb all? After all it has a high need for energy and it can metabolize lactate without a problem. How important is it to ‘prime’ the system for adapting to shifts in metabolic substrates throughout the body? During exercise we see the flow of lactate reversed from circulation to the brain.

Is it comparable to a throttling car? It is much easier to start driving when already throttling compared to a cold engine that is not running at all.

References

“Monocarboxylate Transporter 1 Deficiency and Ketone Utilization” https://www.nejm.org/doi/full/10.1056/NEJMoa1407778

“The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis” https://ashpublications.org/blood/article/106/13/4034/133232/The-energy-less-red-blood-cell-is-lost-erythrocyte

“Long-Term Glucose Starvation Induces Inflammatory Responses and Phenotype Switch in Primary Cortical Rat Astrocytes” https://link.springer.com/article/10.1007/s12031-021-01800-2

In the next part I’ll go a bit more in depth and show what implications it has in practice.

Mechanisms

Glucose metabolism

Lactate is produced in cells through glycolysis. In the cytosol, glucose gets broken down to pyruvate. Pyruvate gets broken down further to lactate (referring to it as cytosolic glycolysis (cGY)). But for the majority of pyruvate is imported in the mitochondria where it is further converted to acetyl-CoA and processed in the TCA to produce much more ATP (mitochondrial glycolysis (mGY)). So only cGY produces lactate.

Response to lactate

Important to know is that MCT1 (and MCT4) can be quickly upregulated. Especially during exercise this is needed but also during acute issues in metabolism. Lactate is an acid and would lower the pH of the cytosol while this needs to be kept in balance. The lower the pH, the more spontaneous reactions happen while it has to be kept under control.

“Exercise rapidly increases expression of the monocarboxylate transporters MCT1 and MCT4 in rat muscle” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665342/

GLUT1 expression

As mentioned earlier, lactate may increase GLUT1 expression which seems like a logical consequence. Under stimulation of hypoglycemia, the blood-brain-barrier increases GLUT1 concentration to increase glucose uptake. It needs a signal to do this.

“Blood-brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited” https://pubmed.ncbi.nlm.nih.gov/9886075/

“Chronic hypoglycemia increases brain glucose transport” https://pubmed.ncbi.nlm.nih.gov/3532819/

During exhaustive exercise, the rat brain has upregulated GLUT1 in the cortex.

“Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity” https://www.pnas.org/content/114/24/6358

Cells that experience hypoxia upregulate GLUT1 expression as we can observe in cancer cells. Hypoxia itself is directly responsible for this.

“Hypoxia and Mitochondrial Inhibitors Regulate Expression of Glucose Transporter-1 via Distinct Cis-acting Sequences” https://www.sciencedirect.com/science/article/pii/S0021925818877146

Rats that are put on a ketogenic diet have an increased brain uptake of glucose (and acetoacetate). They found a 2-fold upregulation of MCT1 yet no increase in GLUT1 in the following study.

“Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats” https://pubmed.ncbi.nlm.nih.gov/21605500/

So it remains to be seen if GLUT1 upregulation is only due to hypoxia or if it can be done by lactate itself but perhaps requires a certain minimum dosage. A last paper on this topic did note an increase in GLUT1 expression in all cases when testing glucose deprivation and hypoxia separately and combined.

r/ketoscience - Keto increases the ability to receive glucose in the brain?

“Glucose deprivation and hypoxia increase the expression of the GLUT1 glucose transporter via a specific mRNA cis-acting regulatory element” https://onlinelibrary.wiley.com/doi/pdfdirect/10.1046/j.0022-3042.2001.00756.x

Again, we see an adaptation when cellular ATP production is impaired, the cell tries to increase influx of substrates that do not require oxygen to produce ATP. Glucose, lactate, BHB fit that job. ATP shortage needs to be fixed acutely.

Glucose sparing

Once BHB can enter the cell, it helps to save glucose usage. We see this for example in CD8+ T-cells where it helps them build up a glycogen buffer.

“Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8 + T-cell memory development” https://pubmed.ncbi.nlm.nih.gov/31871320/

A test in mice muscle showed a statistical effect as of 4mmol/L BHB post-exercise. They have a fast metabolism so potentially require higher levels versus humans.

“Effects of β-hydroxybutyrate treatment on glycogen repletion and its related signaling cascades in epitrochlearis muscle during 120 min of postexercise recovery” https://cdnsciencepub.com/doi/10.1139/apnm-2018-0860

Metabolic emergencies

When ATP supply is in danger, it is a metabolic emergency. We see this reflected in a couple of situations.

The failing heart

Different papers have come out showing increased ketogenesis and/or support from ketones under conditions of a failing heart.

“Ketone bodies for the failing heart: fuels that can fix the engine?” https://pubmed.ncbi.nlm.nih.gov/34456121/ – “Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients” https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.036459 – “Ketone therapy for heart failure: current evidence for clinical use” https://academic.oup.com/cardiovascres/advance-article-abstract/doi/10.1093/cvr/cvab068/6168424 – “Blood ketone bodies in congestive heart failure” https://pubmed.ncbi.nlm.nih.gov/8772754/ – “The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6478419/ – “Nutritional modulation of heart failure in mitochondrial pyruvate carrier–deficient mice” https://www.nature.com/articles/s42255-020-00296-1

Different scenarios for failure exist but animal models show a reduction in fatty acid utilization.

“Beta-Hydroxybutyrate, Friend or Foe for Stressed Hearts” https://www.frontiersin.org/articles/10.3389/fragi.2021.681513/full

Acute heart failure is presented with increased lactate. I would guess the source of lactate is from the heart but with a failing heart, hypoperfusion could lead to systemic lower oxygen which would affect all cells in the body. In this paper they noted the increase in lactate without hypoperfusion.

“Increased blood lactate is prevalent and identifies poor prognosis in patients with acute heart failure without overt peripheral hypoperfusion” https://pubmed.ncbi.nlm.nih.gov/29431284/

It is guess work until I find better evidence but my thought is that the shift away from fatty acid oxidation will result in a higher lactate production to make use of the triad to bring in BHB. What is wrong with the heart that it cannot utilize fatty acids though? Or is it a deliberate shift?

Hypoxia

Just on a side note, lactate production, in response to hypoxia, stimulates angiogenesis. A neat way to prevent future hypoxic events. Lactate has many different roles, we’ve come a long way from seeing it as purely a waste product to how we know it today.

“A lactate-induced response to hypoxia” https://pubmed.ncbi.nlm.nih.gov/25892225/

When mice were stressed under hypoxic conditions they could see an improved tolerance. They had to combine iv glucagon and BHB because each alone did not improve tolerance. This is when they wanted to mimic the improved tolerance that is observed under fasting conditions under which glucagon and BHB are increased.

“Hypoxic tolerance enhanced by beta-hydroxybutyrate-glucagon in the mouse” https://pubmed.ncbi.nlm.nih.gov/6775395/

Further study of squirrels and rats indicate survival time linked to the level of BHB reached in the blood.

“Beta-hydroxybutyrate and response to hypoxia in the ground squirrel, Spermophilus tridecimlineatus” https://pubmed.ncbi.nlm.nih.gov/2364670/

In the following paper, the observed a lower circulating lactate level under hypoxic conditions (4.7 mmol vs 6.1 mmol) when comparing the KD with standard (high-carb) in rats, showcasing the ATP that is derived from ketones as a rescue of the metabolic emergency.

“Adaptation to Chronic Hypoxia During Diet-Induced Ketosis” https://link.springer.com/chapter/10.1007/0-387-26206-7_8

An other test on humans was performed to see how cognitive impairment is impacted by acute hypoxia, specifically due to reduced ATP production. A ketone ester (exogenous ketones) restored cognitive performance.

“A Metabolic Intervention for Improving Human Cognitive Performance During Hypoxia” https://doi.org/10.3357/AMHP.5767.2021

Non-alcoholic fatty liver (NAFLD)

Hepatic insulin resistance is part of NAFLD. Knowing that glycogen synthesis requires insulin, it should not be a surprise to observe higher lactate production by the liver due to lack of glycogen buildup.

In the following study in NALFD patients the hepatic lactate production was even higher before a KD diet. The KD diet resolves insulin resistance so we can expect glycogen to build up in these NAFLD patients but not much. A KD still requires low glycogen levels so the liver remains a source of lactate production.

“Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease” https://www.pnas.org/content/117/13/7347

Ketogenic diet

Under normal circumstances, the brain is already producing lactate in surplus so that there is an efflux from the brain to the blood circulation.

“Lactate transport and signaling in the brain: potential therapeutic targets and roles in body–brain interaction” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426752/

“Striking differences in glucose and lactate levels between brain extracellular fluid and plasma in conscious human subjects: effects of hyperglycemia and hypoglycemia” https://pubmed.ncbi.nlm.nih.gov/11891432/

Under a ketogenic diet we generally see a reduction in glucose roughly as of >= 1mmol/L BHB (anecdotal observation). The brain can’t rely on fatty acids from the circulation so it would end up in energy starvation. On top of that, the skeletal muscle also needs to deal with the reduced glucose availability.

As we have seen above, this would start to deplete the glycogen in the cells so you get an increase in lactate production.

If the skeletal muscle would do this then it would also absorb the BHB that the brain is in need for. Instead, a ketogenic diet increases fat utilization in the skeletal muscle. This reduces the glycolytic action on glucose and thereby reduces lactate production so that it lowers MCT1 expression and lowers uptake of BHB.

The brain however, lowered in glucose affecting glycogen, does increase lactate production so that it can increase BHB uptake.

So everything balances out nicely.

The liver

NADH accumulation from beta-oxidation interferes with pyruvate formation. This essentially blocks gluconeogenesis from sources that require this step such as lactate.

NADH slows down the TCA so that acetyl-coa can pile up and can be used to form HMG-coa to push it further towards ketogenesis.

“Ethanol Alters Energy Metabolism in the Liver” https://www.ncbi.nlm.nih.gov/books/NBK22524/

Especially on a ketogenic diet, exercise will generate more free fatty acids that reach the liver. This is because exercise increases fatty acid release and heart rate causing a faster circulation.

Exercise (on a ketogenic diet)

I had a couple of max effort tests to check on my condition. This gave me the chance to compare lactate before and on a ketogenic diet. The grey line on the graph is on keto. At the early stage you can see how lactate is kept lower until 170 where it goes on par with the result from 2016 and as intensity goes up further, keto bypasses 2016.

Why am I showing this? During the first part, as intensity goes up, you see how lactate is kept lower thanks to relying more on fat but as intensity goes up further, reliance on glucose starts to increase. Because glucose in the circulation is lower, glycogen consumption now starts to increase at a higher rate. When we reach the highest intensity, on KD we are reaching lowest levels so most lactate production.

As you could read earlier, the brain needs the BHB and glucose. When we start exercising, lactate production goes up so the skeletal muscle will take up more BHB while also taking up glucose. That is a problem for the brain if it would not be compensated somehow.

The brain can also utilize lactate as a fuel. So we end up with a situation where the skeletal muscle exchanges lactate for BHB and the brain has to change BHB for lactate.

“Lactate transport and signaling in the brain: potential therapeutic targets and roles in body–brain interaction” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426752/

This process is supported by the liver which reduces its lactate utilization for the gluconeogenesis (GNG) process. Instead it relies more heavily on glycerol for GNG which does not require the step to convert to pyruvate. This step is what is impacted under increased NADH availability. So we see that the liver is sparing lactate for the brain (and is itself even a source of lactate).

Glycogen utilization

A word on glycogen utilization though. It is assumed that on a KD, it spares muscle glycogen. I would argue yes and no.

A first element to take into account is that as glycogen levels start to decline, its utilization is slowed down. This is independent of diet.

A nice experiment was done by looking at glycogen utilization between 2 legs in the same subject. 1 leg started with reduced glycogen while the other leg didn’t. They observed a 60% reduction from glycogen in the ‘reduced’ leg while it took up 30% more glucose. Because arterial supply was the same, this effect could be fully attributed to the glycogen level.

“Effect of muscle glycogen on glucose, lactate and amino acid metabolism during exercise and recovery in human subjects” https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC2269057/

A paper from Timothy D. Noakes et all. also shows this reduced utilization. This could be wrongly interpreted as a glycogen-sparing effect of the ketogenic diet but note the lower level of glycogen that the KD group started with.

“Gluconeogenesis during endurance exercise in cyclists habituated to a long-term low carbohydrate high-fat diet” https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP271934

In contrast, a paper from Jeff Volek et all. shows equal utilization. This could incorrectly be interpreted as that there is no glycogen-sparing effect from the KD.

“Metabolic characteristics of keto-adapted ultra-endurance runners” https://www.metabolismjournal.com/article/S0026-0495(15)00334-0/fulltext

What should be taken into account is the intensity at which ATP needs to be generated. When intensity goes up but mitochondrial ATP production is covering the majority requirement then glycogen utilization will be equal among diets.

However, when intensity goes up mitochondrial ATP will not be sufficient. This is where fat metabolism and glucose metabolism make a difference. Glucose metabolism via mitochondria can be sustained at higher levels although yielding lower ATP amounts compared to fatty acids.

The result is that at very high intensities, glycogen will deplete faster on low carb. Circulating BHB will balance out this situation providing an alternative substrate for the TCA to increase mitochondrial ATP production.

Either BHB or medium chain fatty acids (MCFA) are able to support this action. MCFAs are not impaired for import like LCFAs are.

So does a KD help save muscle glycogen? There is no saving effect at low- to medium-intensity but at high-intensity BHB (and MCFA) do fulfil that role. That is, out of necessity. It doesn’t save glycogen more than high-carb but this is where optimization can help via exogenous ketones or MCT oil.

—- T H E – E N D —-

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