We are now in the year 2020. A lot of research has been performed regarding different diets yet still so much controversy exists around whether or not we should eat a lot of carbohydrates or fat or protein. Those are the 3 macronutrients that are played around with in research. Diets with different compositions compete with each other for being the best at weight loss, health and longevity.
So will I be able to provide a definite answer? I cannot claim that I do but I will present you the material I have been able to gather to provide a picture that will hopefully bring more clarity (and probably as always a lot of questions too).
I have always been interested in health and in lifespan. Healthspan means to stay as healthy as possible for as long as possible and minimize the time in which health deteriorates followed by death. It is my suspicion that if we can live optimally by increasing our healthspan then we may also be pushing our lifespan to what we are naturally capable of.
This has brought me to the point where it is important to know how all of the cells within the human body work together and what makes each cell survive individually.
In order to get a good picture of things, there are a few individual concepts that we need to go through before we can talk about a potential way to affect our health- and lifespan positively.
What are we?
It may come as a surprise to some but “we”, “you” and “I” don’t really exist. Our body is a cooperation of cells. Throughout evolution individual cells have started to form bodies in order to increase their chances at survival and reproduction. In its most rudimentary form these bodies have helped to avoid being destroyed, being eaten or damaged by environmental elements and also helped in waiting for more ideal times to replicate.
Replicating is the essence of life.
It feels strange to think that everything we do in our lives, the complexity of our society, is driven by the desire to survive and reproduce by the billions of cells that we are made up of.
But it is true, the cells that we are made out of are the actual life forms.
Via the book “Lifespan: Why We Age–And Why We Don’t Have to” of author David Sinclair, PhD. it became clear that cells have 2 distinct states in which they operate. They are either running in a mode of repair and maintenance or, when the times are right, they turn to proliferation. When they proliferate, the cells spend much less of their energy on repair and maintenance. All energy goes to creating the building blocks for new versions of themselves.
The Hayflick limitation
The cells in our body are continuously proliferating. All of our organs are undergoing cell renewal to some degree although brain cells practically don’t as everything we’ve learned and remember depends on the connections between the cells. If such a cell would die then that memory connection is lost.
With each cell division, the telomeres that protect the unraveling of the DNA in our cells, gets shorter and shorter. When it is too short, the cell fails to replicate. This effectively puts a limit to how many generations can exist.
When that limit is reached the cell will become senescent over time. It will gradually lose its identity. Although all cells have the same DNA in their nucleus, they all differentiate into a specific cell type (a heart cell, lung cell, muscle cell etc). Throughout time, the cell will accumulate DNA damage causing it to behave differently and lose that identity.
There are possibilities for cells to overcome this limit because we have an enzyme called telomerase which repairs the telomere ending of our DNA. In humans we primarily see this in cancer and stem cells. Both types are undifferentiated to some degree which suggest that it is important to limit growth when the cell is part of a community such as an organ.
So what does this tell us with respect to health span? It is important to spare ourselves from DNA damage and mutations to stay healthy and when we are grown up, if we can slow down the cell replication over time, then we are adding time to our existence so prolonging our lives.
How can we achieve this? By reducing cell replication we automatically drive up the potential for cell maintenance and DNA repair.
One of the ways that DNA is repaired is by a group of enzymes called sirtuins. The enzyme SIRT1 performs repair at the nucleic DNA. The activity of SIRT1 is regulated by the ratio NAD/NADH. A higher NAD availability is required for SIRT1.
A cell that is stimulated in metabolism has a lower SIRT1 activity. This metabolism is modulated by our thyroid hormone free T3 (fT3) so a potential suggestion is to reduce this stimulation. fT3 stimulates cell proliferation as shown in different cell lines, which is opposite of what we want to achieve.
“3,5,3′-triiodothyronine (T3) stimulates cell proliferation through the activation of the PI3K/Akt pathway and reactive oxygen species (ROS) production in chick embryo hepatocytes” https://pubmed.ncbi.nlm.nih.gov/22366194/
One of the ways to reduce fT3 is to reduce caloric intake. This has been shown successful in many different species to extend lifespan.
Caloric restriction definitely does its job by increasing SIRT1 activity and NAD availability. This is not the case in all tissue according to this study. They noted a lower ratio in the liver while the muscle and white adipose tissue both had increased ratios.
But is it achievable to subject ourselves to a lifelong caloric restriction? It comes with a whole host of side effects such as fatigue, feeling cold, feeling hungry and if pushed too far then it is also detrimental for your psychological well being.
It could be manageable to live in a warm climate so the reduction in body temperature is less of an issue but still the lack of energy, possible mental impact and hunger feeling will remain a challenge.
Growth stimulating hormones
There are 2 other important hormones affected by caloric intake and those are insulin and IGF-1.
“Insulin-Like Growth Factor-1 Promotes G1/S Cell Cycle Progression through Bidirectional Regulation of Cyclins and Cyclin-Dependent Kinase Inhibitors via the Phosphatidylinositol 3-Kinase/Akt Pathway in Developing Rat Cerebral Cortex” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256126/
It is not a coincidence that food intake drives up metabolism via these hormones and T3. When nutrients become available, it is an ideal moment to proliferate, to replace malfunctioning cells with new ones. The cells that make up our body see this as a signal to grow.
Carbohydrates and protein are responsible for insulin and IGF-1 stimulation for the biggest part.
Our current diet causes chronic inflammation which requires renewal of cells but also tends to build up insulin resistance over time. The muscle and liver are the highest recipients of insulin-driven glucose uptake. Over time they become resistant leading to prolonged elevated levels of insulin which affects all cells in the body.
Protein itself stimulates IGF-1. Dietary protein delivers the cells the necessary building blocks to function. The amino acids that make up the protein can even stimulate the thyroid to produce more fT3.
It looks like we have no choice! We can’t live without food and when we take in food we stimulate the growth mechanism. Although it is correct that we can’t live without food, the composition of our food can be changed in such a way that we benefit the most from it in terms of health span.
Can we somehow reduce metabolism while remaining warm, energetic and mentally focused?
In order to keep warm, we can look at what animals do in colder more northern climates.
When we compare animal life in a warm climate versus a cold climate then we notice a change in survival strategy. In cold climates, surviving the next day does not depend on food but on heat production and protection from cooling down and freezing to death.
The answer that nature has provided to us is fat. By developing a subcutaneous layer we have created a bit of insulation. But insulation is nothing if both sides of the layer are equal in temperature so we have our own heat production (thermogenesis) as a second important component.
That heat production is not a static element. It can be intensified via cold exposure but also by consuming high amounts of fat. The traditional Inuit diet consists of high amounts of fat. One of the side effects of consuming a diet low on fat is that they feel colder due to it.
“We were really getting three-quarters of our calories from fat.”
Given the above info regarding metabolism, having a higher production of heat thanks to consuming fat would give us a way around the colder body temperature that is normally part of a lower metabolism. That is, if this fat consumption does not increase our cell metabolism.
Into a bit of science
Thermogenesis is currently being researched for longevity. This is for other reasons though because the researchers suspect benefits from it by reducing diseases. Although that by itself would also have the potential to help you to extend healthspan, which is certainly what we are after, it may not necessarily indicate an extension of lifespan.
One interesting bit from the article is the following:
thermogenic adipose tissue activation in response to cold exposure induces the release of eosinophil-activating cytokines by type 2 innate lymphoid cells.
Type 2 innate lymphoid cells (ILC2) will be present in the lungs to surveil potential viral infections. When they pick up the relevant signal, they’ll stimulate mucus production and also increase other effects such as memory b-cell recruitment.
Stimulated by IL-33, these ILC2’s are also required to convert white adipose tissue into beige (due to the increase in mitochondria).
When we further investigate, we see that there is an increase in uptake of T4 into the brown and beige adipose tissue under stimulation of the sympathetic nervous system. This T4 is locally converted into T3 to drive up the metabolism of the fat cell itself and thereby its heat production.
This is very interesting as it gives us a clue on how this higher metabolism is achieved. Not by stimulating metabolism overall in the body but very much focused in fat cells themselves.
I can only speculate about it but by taking up more T4, there is less conversion towards T3. This could be counteracted by increased T4 production. What it could mean is that at least we don’t have a systemic increase in metabolism in order to increase warmth production.
Interestingly all these effects also take place during cold exposure.
What does it all mean?
If longevity depends on reducing growth and health depends on the time spent in maintenance/repair then a very high fat diet could be a possible solution.
I’ve only covered the metabolic part in this article but the consequences reach further than just metabolism. By making the switch from primarily glucose to primarily ketones and fat we can modulate what happens inside our cells.
As indicated under the section “Cell Metabolism”, nuclear DNA repair is mediated by SIRT1. Intrinsically linked, a very high fat diet raises SIRT1. We can see this already in the brain of mice but there is other research indicating the same.
I’m saying intrinsically because a reliance on fat and higher dietary fat intake seems to signal to the overall organism that our body is that times are not right for reproduction, that we are living in a tougher climate so that time is better spent on repair and maintenance.
Rather than mimicking starvation, to me the overall picture looks like a high fat diet is meant to sustain life through cold climates. Fat is THE energy source in winter.
The activation of the ILC2’s represent a higher surveillance against viral infections. Respiratory infections is something we see typically return every winter.
Increased heat production is required to survive the cold through the night and through the day. We don’t need this anymore today but it was necessary in our past.
Winter typically is harder to hunt and find food. The extra fat mass in our body helps to endure sporadic tough days.
Sporadic because in our past there were large mammals available who delivered a big volume of fat. Our food during winter likely was always high in fat availability.
Keep in mind though that a very high diet does mean consuming a lot of fat. Not just avoiding carbohydrates. Frequently people are afraid of calories and think they will gain from it.
If you keep carbohydrates out of your diet and keep protein intake to a minimum then you fill up the rest with fat to satiety. If you don’t eat enough fat, you will feel cold.
Keep in mind the rhesus monkeys, they had a 13% lower metabolism. Estimations of increased energy metabolism on a high fat diet are indicating +/- 12% extra metabolism on top of a normal diet.
As a wild guess, we can compensate for the reduction in metabolism by letting thermogenesis cover an extra 29% of calories.
2000kcal – 13% = 1740kcal (on reduced metabolism)
2000kcal + 12% = 2240kcal (on a very high fat diet)
The experiment in mice showed a state that mimics caloric restriction yet showed an 11% increase in metabolism, primarily due to heat production.
I’ve been interested in cancer for quite a while. Even before I got affected, the complexity and the link with metabolism caught my attention. Despite digging up all the details of how cancer develops and works, I somehow never could find a distinct feature of a cancer cell. I could not find a single feature that I could not find back in other normal cells.
They do what is normal for growing cells, they do what is normal for cells under hypoxic conditions. They behave similar to embryonic cell proliferation, to immune cell proliferation. Except… they don’t differentiate. Why don’t they differentiate?
“But isn’t it clear” you may ask? “It is a genetic disease right? So mutated genes of course!” Really? Thomas Seyfried already showed that by taking the nucleus (where the cell genes are located) and putting them in another cell doesn’t create a tumor cell. However, putting the mitochondria from a cancer cell into a normal cell does cause the cell to become cancerous.
Mutated nuclear DNA doesn’t seem to cause a cell to be cancerous. The mitochondria however contain mitochondrial DNA. Perhaps mutations there cause cancer? That doesn’t stride well with the way mitochondria work.
They are highly susceptible to damage indeed but through evolution they developed a build-in mechanism to eliminate malfunction parts. Through fission and fusion they continuously break up and digest malfunctioning mitochondria via a process called mitophagy to then build up again towards bigger properly functioning mitochondria.
Then along comes my investigation on the root cause of atherosclerosis and it drives my attention to the role macrophages play in the pathology. There I get to learn about how monocytes get stuck at locations of inflammation via signaling molecules (cytokines). Locally they start to perform their job where they stimulate satellite cells to become active and start proliferating. Again this is happening through signaling via cytokines. The macrophages also change profile in this process. This causes their metabolism to switch from glycolysis towards fat oxidation. And once more this is triggered by external signaling.
After all this comes along a video on my feed in youtube. PhD Mina Bissell from UC Berkeley explains about her life work. She shows how the extracellular matrix (ECM) is driving behavior.
Her work supports Thomas Seyfried. When implanting tumor cells into a chicken wing, it develops like a cancer. Those cells in a petri dish develop like a cancer. Inserted into the wing of an embryo, they behave like normal cells despite having mutated nuclear genes! The context, the surrounding is different, not the cells!
Proliferate or differentiate under influence of the ECM. This is very important. It shows why cell cultures fail to provide similar results in vivo. They are missing the context.
What are the components of the ECM? Here’s a good introductory video.
Notice here lamina which has been central in the work of Bissell.
If you watch the video then notice at some point he says how the structure gives cells some resistance to migrate, they ‘feel’ there is no room to proliferate! The cells ‘feel’ this through interaction with the ECM.
When he discusses proteoglycans, he explains about hyaluronic acid (HA or also known as hyaluronan) and how it attracts water so that together it forms a gel-like structure.
I found the following article a true eye-opener. They did research towards the effect of a breakdown of the HA. When this structure is lost around cells, they change metabolism towards glycolysis and take up an accelerated migration pattern.
When HA is lost, the inhibitory effect on GLUT1 translocation to the membrane is lost. This allows the cells to increase glucose uptake in support of glycolysis. This switch in metabolism is what cells do to proliferate. This is what enables them to turn on the right genes for building copies of themselves and construct the raw material for building these copies. This is not a special feature of cancer and you certainly don’t need a mutated gene.
As you can see in the next picture, every single cell line they tested this with responds in a similar way, starting to increase glucose uptake and increase lactic acid production. They used primary, immortalized, murine, human cells, as well as cancer cells. A very diverse array of nuclear genetic material yet they are all responding.
Loss of HA also allows cells to migrate more which reminds us of metastasis in cancer.
When we look at how muscle repair works then we note a similar behavior for satellite cells (which get activated and proliferate thanks to macrophage signaling). What we note is that amongst others, the ECM factors (collagen, fibronectin) are listed as regulators of their proliferating state. Including beta1 integrin which was used by Bissell.
How much research is done on cells without providing an ECM? Wouldn’t it invalidate their applicability? By not providing an ECM during testing, we know what cells do without it. They proliferate. You don’t need a cancer cell, you don’t need genetic mutations. Trying to develop drugs that interfere with the growth will likely interfere with the growth of all cells. It is not specific enough.
Unless loss of ECM is part of cancer but that is not the case.
But it begs the question, is it possible that the root cause of cancer has to be found in a disturbance in the cell environment? In its ECM?
I suspect a situation of chronic hypoxia in the case of atherosclerosis because the cause of hypoxia is outside of the region that is affected by hypoxia. As a result the region itself tries to recover from it but is unable to.
We have to start somewhere so why not start with the hypothesis that in a similar way there is a disturbance in blood supply to a region in the body. This triggers inflammation and leads to a response to heal. But what if the response is not sufficient to fix the hypoxia? We go from acute to chronic.
Hypoxia certainly affects the ECM. It activates breakdown of the basement membrane while at the same time building up collagen.
What I understand from the basement membrane is that it gives the group of cells their purpose. It helps cells to differentiate, provide structure for organ development and so on. The basement membrane is stabilized by type IV collagen but hypoxia also upregulates type IV collagen-breakdown enzymes (MMP2, MMP9).
One thing I keep reading is how the neovascularization fails. The whole idea is to improve blood supply so that oxygen can be delivered to resolve the hypoxia. But it fails to do this properly.
Although there are manifold VEGF signals sent out for vascularisation, it could be that the proliferation of cells had a chance to build up in volume to interfere with proper development, interfere with the proper structure formation.
Such defect in proper vascularisation could signal the entry into a more chronic state of hypoxia and exposes the inability to resolve the hypoxic situation.
Something goes wrong at the very end of the microvessels, a malfunction of some sort. Because of this, oxygen delivery by the blood fails to reach a very small area which causes that area to become hypoxic.
Similar to atherosclerosis, the cause for the hypoxia is nearby but not in the area itself. This starts to set the normal hypoxia reactions in motion: macrophage attraction, cell growth, ECM remodeling, neovascularisation etc. all the steps needed to resolve the situation and all hallmarks that we are familiar with looking at cancer.
What should stop the growth however is proper vascularisation. But this fails because the cause of the initial damage to the blood vessel is still there. That damaged area is closest to the hypoxic region and from that damaged area it would normally start to grow new blood vessels.
But because the point to start new blood vessels from is also the point that is damaged, the formation of new blood vessels is impaired and is unable to rescue the hypoxic region in time.
Support for the hypothesis
A first detailed look at the situation shows us that loss of fatty acid synthase (FAS) enzyme increases malonyl-coa which acts as an inhibitor for mTORC1. This impairs the ability to grow new vessels.
I know diabetes and hypertension are risk factors for cancer. I’m also aware that diabetes patients risk amputation due to capillary damage.
In the following article they explain the mechanism. FAS binds to Nitric Oxide Synthase (NOS). What they did was knock out FAS in endothelial cells. This caused the blood vessels to become leaky and “unable to generate new blood vessel growth“. This aligns well with the impairment of mTORC1.
I’m not fully clear why but we see higher circulating levels of FAS in diabetes. One possibility that we see is that FAS is mainly produced in the liver and possibly insulin resistance in the liver may cause FAS to be secreted into circulation.
We know smoking is a risk factor for both atherosclerosis and for cancer. Although the following article is about smoking and atherosclerosis, I bring it up because it shows how smoking causes damage to the endothelial cells. Smoke isn’t selective to your heart. It is also increases the risk factor for amputation.
We would expect this in the hypothesis if cancer originates from damaged blood vessels.
Fatty acid types
The following paper found that palmitic acid and linoleic acid cause a similar impairment. Both types of fatty acids are more prevalent in our diet (linoleic acid, palmitic acid) and from endogenous production (palmitic acid) due to a high carbohydrate diet combined with insulin resistance.
The experiment that Seyfried showed us is somewhat a result after the facts. Proliferation is driven by the state of metabolism (glycolysis or oxphos). But the state of metabolism is switched (not driven) by the signals from the environments. In response to this signal, the structure of the mitochondria change to support this mode.
Glioblastoma cells in different ECM mediums (added on 2021.04.07)
The following paper shows nicely how the environment of the cells influences their behavior and morphology. They compared a typical collagen versus a GBM-patient tissue derived ECM. With the picture you can already see how the same implantation of cells proceed differently whereby only the ECM is different.
I do not think cancer nor atherosclerosis can be defined as a metabolic disease because I do not see any impairment in metabolism. It is a problem with oxygen delivery driven by endothelial dysfunction. The nearby affected region is then inflicted with hypoxia which starts to drive the remodeling of the ECM. The remodeling drives the cells to their dedifferentiated embryonic state. The lactate production is to implement attachment as is seen under true embryonic development. Unfortunately, with impaired endothelial cells from which the vascularization should take place, this step of the process fails to be done properly so that the hypoxic situation remains unresolved.
What needs to be cured is endothelial dysfunction.
Current cancer standards of care
If this hypothesis turns out true, the current treatment options for cancer may actually cause cancer through the same mechanism, damage to the blood vessels.
Recently I wrote an article exploring what could be at the root cause of atherosclerosis. After the publication a comment pointed to the macrophage and cholesterol not being discussed. I didn’t do this because the root cause brought me to a point before macrophage and LDL-cholesterol comes into the picture.
But it got me thinking… what about those macrophages? Why do they take up that cholesterol? What are they supposed to do with it? Why aren’t they doing anything with it? Is it normal for them to just sit there and engulf the LDL cholesterol? Do they take up the LDL by accident and this disables them to function?
Nobody seems to talk about the role of macrophages, why is that? Do they do everything as is supposed to in the development of atherosclerosis? How is the LDL causing an issue here? Is it the fault of cholesterol itself that it gets stuck there? Or is there more to it?
They do correlate well with the lipids and severity of the atherosclerotic plaque. Could there be a problem with the macrophages?
I have read my fair share of research in the last 3 years and this gets remarkably little attention but there is no lack of research. As you can see there are a lot of questions to raise and clear up so it is time for another dive into an area where I know nothing about, exciting!
My very basic understanding about macrophages started with them being cells that can kill pathogens and malfunctioning cells by taking them up and dismantling them, releasing the pieces as debris for recycling or elimination by the liver.
I want to start with the result first because there is a lot of ground to cover. The full article is quite detailed so for those who cannot spare the time, here is the result in brief.
Hypoxia causes macrophages to become immobilized. As a first step they become a pro-inflammatory glycolytic M1 type in order to stimulate growth. These M1’s prefer the uptake of oxidized LDL and accumulate their lipid. After a while they should differentiate into the anti-inflammatory M2 type which consumes the accumulated lipids through fatty acid oxidation for energy. This has nothing to do with creating disease but are all part of resolving the inflammatory situation. It is the healing process.
However, although the elements are there to perform this change from M1 towards M2, this process becomes only partially successful resulting in macrophages that fall in between showing properties of both M1 and M2. As a result they maintain M1 features including the uptake of oxidized LDL. The environment signals them in both directions.
My own interpretation of the research lead me to believe that the inflammation as a consequence of the hypoxia is not resolved by the actions of the macrophages although this is what they are supposed to do (as you can see in muscle repair). They normally resolve the hypxia-induced inflammation by resolving the hypoxia through cell regeneration and vascularisation.
If you have read my article on the root cause then you see that the cause is outside of the reach for macrophages to resolve it.
Due to the existence of a hypoxic region at the bifurcation as a result from contracted or hardened cell wall due to factors such as smoking, high insulinemia, fructose etc… You get a region in the blood flow that does not deliver sufficient oxygen to the deepest layer of the intima.
The furthest away from oxygen delivery becomes the most hypoxic and starts to send out inflammatory markers.
Monocytes infiltrate and are immobilized by hypoxia and differentiate into M1 macrophages by the environmental stimulus. As M1 macrophages they take up oxidized LDL so that they can collect lipids to support their proliferation. Normally the further progression of actions from M1 macrophages result in a morphology towards M2 macrophages.
These M2 macrophages use the accumulated fatty acids for fuel resulting in a clearance of the fatty acid content. We see that there is vascularisation penetrating from the vasa vasorum so the initial hypoxic region closest to the media is rescued from that side.
But at the same time the original M1 macrophages also stimulated growth of the intima creating more distance between the hypoxic region and the endothelial wall. On one hand the issue is resolved but on the other hand the problematic area now just shifted further away from the media and still the problem of the reduced blood flow isn’t solved.
Because this issue with the blood flow remains, you get a continuous growth stimulation leading to a further narrowing of the blood passage.
And now for the research that led me to this conclusion.
Where I started
A first thing I did was get me some better background info on macrophages. I know they are part of the immune system so a refresher is always in place. An excellent video to start with for a basic overview is the following.
Important to understand is that, as you can see from the video above, these cells develop and morph into different types. Macrophages circulate as monocytes and when triggered they develop into different types of macrophages.
Next up is a visit to wikipedia on macrophages itself. It has a section on macrophage subtypes but underneath I noticed a section on muscle regeneration. That is interesting. In my root cause research, vascular smooth muscle cells are affected. I know these cells are not exactly the same as skeletal muscle cells but still.. why not have a look at the interplay between skeletal muscle and macrophages. Maybe we can learn something from it.
The next video shows how muscle damage and repair is supported by monocytes-turned-macrophages.
What we can learn here is that macrophages play an active role in the environment and again note how macrophages of the M1 type transition into the M2 type. These are the 2 main categories that I’ll look into but note that there are many sub-categories and versions in between depending on the tissue they are located at etc…
By taking up malfunctioning cells macrophages have learned to extract the lipids for further usage. Related to this, a distinct feature is that M1 types are more prone to fatty acid synthesis while the M2 favor fatty acid oxidation. They operate in a hypoxic area so they revert to glycolysis, something we recognize from cancers cells that also live in hypoxic conditions.
This is offering a first clue as to why M1’s take up lipids. Proliferating cells require lipids to build these new cells. Proliferating cells require lipids for membrane construction and other organelles that also have membranes.
When the monocytes migrate into the inflammed area, hypoxia is one of the drivers to change their phenotype towards M1 macrophages.
These type of macrophages stimulate inflammation in order to trigger proliferation of satellite cells which then further become differentiated and form newly repaired tissue.
These macrophages are also know to stimulate proteoglycans (PGs) to stimulate the buildup of the extracellular matrix which will hold the new tissue. These proteoglycans are the earliest evidence seen of atherosclerosis before lipids accumulate.
Walton  showed this mucoid thickening of the intima occurs before lipid infiltration and is composed primarily of collagen, PGs, and ECM. Thus, although lipid accumulation in the artery wall is considered an early event in atherosclerosis, lipid retention is not the initiating event, and the fatty streak is not the first sign of atherosclerotic injury [11,12].
It tells us that these macrophages arrive to the site of injury and then start to accumulate lipids. This order of sequence is important as some believe LDL gets stuck, oxidizes (or not) and cause inflammation and then macrophages arrive to resolve this.
The correct order is that inflammation attracts macrophages and then they start to accumulate lipids.
This alone is a reason to question if lowering LDL is a meaningful thing to do.
These macrophages are the ones who help the proliferated satellite cells to differentiate and form restored tissue.
One of the contributing factors to make the switch from M1 to M2 is the activation through PPAR-γ and IL-4. PPAR-γ is activated by fatty acids so to no surprise, the M1 needs to accumulate fatty acids in order to transition.
There are different scavenger receptors on the cell surface that take up fatty acids from circulation. LOX-1 and CD36 are 2 types of such scavenger receptors. CD36s are particularly fond of oxidized LDL (oxLDL). Just as they learned to extract fatty acids from dying cells, they also extract the fatty acids from oxLDL. Under normal circumstances, the cholesterol is expelled from the cell and picked up by HDL particles via a process called reverse cholesterol transport.
With such an important function for HDL it should not be a surprise that low HDL is stated as being a strong and independent risk factor for atherosclerosis! But does increasing HDL lower your risk? Attempts have been made and failed to show benefit. Is that a surprise though? Do you expect a fix if the root cause is not addressed?
Interesting to note is that the availability of cholesterol within the cell triggers the transcription to export the cholesterol.
Accumulation of cellular cholesterol leads to activation of several transcription factors, including PPARγ, LXRs and RXRs which subsequently regulate expression of their target genes including transporters such as ABCA1 and ABCG1 which regulate the efflux of free cholesterol and scavenger receptors. Alternatively, passive efflux of free cholesterol can also occur.
So the idea is to export cholesterol yet we do find cholesterol back in the plaque so it seems that yet again the unresolved hypoxia is playing a disturbing factor.
But back to the oxLDL…
In areas of low oxygen you get an increase in ROS production which interacts with the LDL to oxidize it. Being in an environment with high risk of oxLDL, macrophages prefer oxLDL. That is not a coincidence.
oxidized LDL has also been reported to induce the expression of the M2 macrophage phenotypic marker arginase 1 via activation of peroxisome proliferator activated receptor-γ (PPARγ)79, and oxidized phospholipids present in oxidized LDL induce a macrophage phenotype distinct from M1 or M2 that has been termed Mox, which is characterized by increased expression of nuclear respiratory factor 2 (NRF2)-dependent genes and reactive oxygen species80. It is likely that T helper 1 (Th1) and Th2 cells in plaques secrete macrophage-polarizing factors81 that also contribute to the balance of M1 and M2 macrophages. Nonetheless, the factors in the plaque microenvironment that promote the polarization of these cells in vivo remain incompletely defined.
This is a difficult area to conclude from because of its complexity but we can already see that oxLDL is a factor that contributes to the change away from the pro-inflammatory M1 type. Rather than considering oxLDL an issue, it may even be a necessary factor in the path towards tissue repair and resolution of the inflammation. But why aren’t they moving towards M2?
Why don’t they change to M2?
In order to have a possible answer I first looked at some info again on how this is handled in muscle tissue.
We see here that BACH1 is an inhibiting component for the transcription to move towards the M2 (repair macrophage) type. BACH1 gets inhibited by binding to heme.
Heme itself gets degraded by Heme Oxygenase 1. This enzyme gets upregulated by oxLDL but also by hypoxia and we see this in the plaque.
HO-1 is transcriptionally upregulated as a sensitive antiinflammatory protein by various types of oxidative stress, such as oxidized LDL,14 ultra-violet radiation,15 thiol scavengers,16 and hypoxia,17,18 as well as substrate heme19 in the cardiovascular system.
There are likely other factors but this again makes an important link with hypoxia. If the status of hypoxia cannot be resolved then this creates a chronic situation of more prevalent M1 macrophage phenotypical lipid uptake.
But the factor of oxidized LDL is also intriguing so I took a closer look at the reference. It seems there are specific molecules required in the oxLDL to trigger HO-1. This may actually represent an issue in the research as there are many ways to create oxLDL. Preferrably the test is done with oxLDL extracted from human sera.
Lysophosphatidylcholine, one of the major components present in oxidized LDL, was ineffective to induce the gene expression, suggesting that other lipophilic substances derived from LDL oxidation are responsible for the induction of HO-1
A reason why macrophages stay where they are is because of hypoxia but also cholesterol accumulation induces expression of netrin 1, a molecule that prevents them to migrate. This is very important because as I showed in my previous article, there may be a chronic situation of hypoxia that initiates the rest of the pathology.
Macrophage expression of these migration inhibitory molecules are also induced during hypoxia, which is intimately linked to atherosclerosis26,95
In the process of resolving the situation there is vascularization, small micro vessels that are formed to feed the affected area so that it can receive nutrients and oxygen. This is how muscle develop and become stronger.
What would happen if that situation of hypoxia cannot get resolved?
Some people on a ketogenic diet see their LDL cholesterol increase dramatically (typified Lean Mass Hyper Responder or LMHR). Levels above 300mg/dL is not unusual but typically they also see their HDL double compared to the days they were on a high carb diet.
Naturally such people are severely encouraged by their doctor to either quit the diet or use statins to lower the cholesterol because current assumption is that it causes atherosclerosis.
One of the elements in the physiology is that this CD36 receptor is enhanced by skeletal muscle. This means that if oxidized LDL is part of the issue, more of it is taken up by the skeletal muscle for energy usage.
OxLDL is no stranger to the body so is it really just bad? With my current understanding I suspect that the body has foreseen a way to make it part of the overall functioning. The oxidized form may no longer be able to perform the same functionality as LDL so rather than throwing it away, cells have developed a way to use the fatty acids that it contains.
This would be ideal and could explain the preference of the CD36 receptor for oxLDL. Recuperate what is possible. They contain energy which helps survival. Being on a ketogenic diet you especially depend on fatty acids for energy production so our LMHR’s could be clearing more of these oxLDL from the circulation leading to an overall lower level.
But we can only claim this if there is no proportional increase in oxLDL as a percentage of total LDL.
“Muscle-specific overexpression of FAT/CD36 enhances fatty acid oxidation by contracting muscle, reduces plasma triglycerides and fatty acids, and increases plasma glucose and insulin” https://pubmed.ncbi.nlm.nih.gov/10480880/
And again, such affinity for oxLDL by the CD36 scavenger has a reason so oxLDL must be part of the design. It cannot be bad by itself but perhaps in the quantities that it is present, it may overwhelm the system.
expression of the fatty acid translocase Cd36 gene was higher in the LCHF group (mouse study)
Previously, we reported that FoxO1 activation in C2C12 muscle cells recruits the fatty acid translocase CD36 to the plasma membrane and increases fatty acid uptake and oxidation. This, together with FoxO1 induction of lipoprotein lipase, would promote the reliance on fatty acid utilization characteristic of the fasted muscle.
It makes me suspect that absolute levels of oxLDL are more important than your LDL-c level.
The following article even shows that the LDL receptor is downregulated (!) in macrophages so that non-oxidized LDL have a more difficult time being absorbed while the scavenger receptors are not downregulated.
among 425 patients with acute coronary syndrome (ACS), the HR of AMI recurrence or ACS-related death at the 5-year follow-up was 2.88 (95% CI: 1.93–4.32) for 1 mmol/L increase in circulating ox-LDL
When a hazard ratio goes above 2 then it gets me interested for a possible link. The article discusses other studies that showed no meaningful HR so we have to be careful here and look at each study to see what differs between them for reaching different conclusions. It could also show that oxLDL is just one factor of many that make up the pathology of atherosclerosis.
The article continues to show that different statins are able to lower the volume of oxLDL. So if statins exert an effect, is it because they lower LDL cholesterol overall or because they lower oxLDL?
A different paper reports on the ability of Atorvastatin to suppress the uptake of oxLDL by macrophages and at the same time lowers their CD36 expression.
Whatever the answer, it doesn’t change the observed mechanism of reduced uptake of normal LDL. And with how statins exert their effect, should we consider our total LDL-c level as an issue?
I’m more inclined to focus on oxLDL. Not to eliminate it but to reduce quantity.
Also when we see the role that HDL has to play, we can conclude it is not necessarily the cholesterol itself that can form an issue. LMHR’s more often than not have very high HDL cholesterol to assist in this uptake from cells that do not need the cholesterol such as the macrophages. But since all cells that have increased their dependency on fat metabolism have increased uptake of oxLDL, there could simple be more HDL required.
Is the level in function of how much is needed? We can’t be too quick to conclude. They don’t necessarily have a higher availability for cholesterol uptake by HDL from macrophages.
This is a very difficult area of research I think because it will all come down to the rate at which this happens and the amount of oxLDL that is in circulation.
Furthermore the cholesterol efflux speed depends on the ABC1 transporter which is down regulated by unsaturated fat, not saturated fat. The ketogenic diet favors more on the side of saturated or mono-unsaturated fat and certainly promotes avoiding poly-unsaturated fat.
What would I recommend knowing what I know so far? Handle the root cause and don’t worry about cholesterol but do look into what causes LDL to oxidize. Check out my article on oxidized LDL for some of the protective factors. You can find them more towards the end.
I hope this article has given you again some more background on how things work and help you in your search to be in control of your health.
Medical establishment considers a causal role for cholesterol. There has been a great deal of effort put into lowering cholesterol without significant effect on curing and preventing the disease. How come the failure is so big? Is it really THE cause? I’m especially concerned because my LDL level is >300mg/dL
It turns out that the exact cause is unknown.
The exact cause of atherosclerosis isn’t known. However, studies show that atherosclerosis is a slow, complex disease that may start in childhood. It develops faster as you age.
Atherosclerosis may start when certain factors damage the inner layers of the arteries. These factors include:
Despite being unknown, a number of factors are listed that damage the arteries. As you can see it mentions high amounts of certain fats and cholesterol.
What is really at the basis? Is cholesterol a necessary component? Throughout the years I have seen a lot of material to compose a fairly descent picture today. I’ll present it as the step-by-step discovery, the way I did…
Atherosclerosis is recognized by a number of properties so we can start by looking into some of them and deviate as we pick up the breadcrumbs:
Where does the plaque come from? Foam cells that make up the plaque are macrophages that are stuffed with lipids, primarily oxidized LDL. Here we see why LDL cholesterol is claimed to be bad. It is in fact not the LDL cholesterol but the entire LDL particle so why single out only one of the elements that it is carrying?
One of the contributing elements for macrophage uptake of oxidized LDL is hypoxia (low oxygen levels).
But if I were to believe the information on wikipedia, one of the first things in atherosclerosis is macrophage infiltration in conjunction with foam cells. Could hypoxia already be present from the start? And what causes these macrophages to infiltrate in the first place? What attracts them?
Hypoxia before or after, it seems to have a major impact. In a mouse model of atherosclerosis, disabling HIF-1a they were able to reduce atherosclerosis by 72% ! HIF-1a is stabilized under low oxygen levels and sets a whole host of changes in motion to help the cell survive and signal distress through inflammatory markers.
And one more effect of low oxygen levels is the stimulation for growth. Again also here we see this happening in cancer. A lack of oxygen leads to glycolysis, the production of ATP from glucose without oxygen, which increases ROS production and this sets a transcription in motion of different genes that are specific for growth. The growth happens in the tunica intima layer mainly although it is also observed in the areas close to it.
The intima is a layer that grows thicker with age.
What we have seen so far are effects that have their origin in hypoxia. But does that mean hypoxia is the cause? Even if hypoxia can be established as a causal factor, what would cause the hypoxia? In order for any of the contributing factors to result in hypoxia we must find a link somehow. Below are 2 factors that we can look into as mentioned at the beginning.
This paper shows how nicotine causes senescence in vascular smooth muscle cells (VSMC), the cells that make up the tunica intima (but not only the tunica intima).
What is important is then to look at what senescent cells trigger. They send out scenecent-cell-specific signals that will attract macrophages. This will lead to the destruction of the cells by the macrophages. Interesting, because now we see at least that there are causal factors for attracting macrophages before they infiltrate and accumulate LDL particles.
Depending on whether MOs are in the classically-activated M1 or alternatively-activated M2 states, MOs can promote cell death through either cytotoxicity or phagocytosis, respectively. MOs in the M1 state secrete TNFα, IL-1β, and IL-6, potentially amplifying effects of the SASP [140,141].
But does this cause hypoxia? And VSMCs are responsible for the contraction and relaxation of the artery but then again they are lining up throughout all the arteries so do we have atheriosclerosis all over the place?
Atherosclerosis is not found all over the place. It is primarily seen at specific areas in the arteries. Namely at the bifurcations.
This has been investigated and the reason why it occurs there has to do with the shear stress. Measured in subjects with CVD in the carotid intima we see a lower level of shear stress compared to healthy individuals.
The bifurcation areas are specifically prone to low endothelial shear stress. That is to say – under certain conditions –
These areas of low shear stress at the bifurcations causes lower oxygen delivery to the arterial wall so we get to understand why hypoxia could be involved.
Arterial Wall stiffness
OK so far we understand why it happens where it happens but we haven’t differentiated on why it happens in some people and not in others. But first, the shear stress is something that is negatively correlated with the elasticity of the arterial wall.
There are other effects at play with VSMC than senescence as we saw under smoking. They can change their phenotype from contractile towards proliferation depending on signaling that takes place. A loss of function sort of.
What do we have so far? Most of the noted effects such as plaque buildup, hyperplasia, angiogenesis are all factors due to hypoxia. The hypoxia result from regions in the artery that are prone to result in low shear stress regions. But before we get such regions there must be factors that cause the reduction in elasticity, which means factors that affect the functioning of VSMCs.
We’ve seen smoking causes scenescence of VSCM so that they reduce their elasticity. But are there other damaging effects that can cause VSCM to become inflammatory and start to function badly?
I mentioned smoking and sugar earlier on but haven’t touched on sugar yet so here we go…
Knowing what we know so far, we could ask the question why insulin resistance (caused by sugar) is a contributing factor. Does it affect the VSCM? Does it lead to wall stiffness? Does it lower oxygen in the blood?
What is specific about the effect of insulin is that it lowers the ability to survive for the VSMC so any negative effect on VSMC and insulin may reduce their recovery.
I’ve already referred to the following article but wanted to quote on the factors that lead to VSMC dysfunction (loss of contractile function):
Key pathological factors associated with diabetes mellitus including high glucose (HG), advanced glycation end products, growth factors, and oxidized lipids promote VSMCs dysfunction by enhancing inflammatory gene expression, migration, and proliferation via activation of multiple signal transduction pathways and downstream transcription factors.
Although not related to the stiffness there is more in the way fructose contributes to atherosclerosis. I also mentioned the oxidized LDL at the beginning which macrophages take up with higher affinity. Fructose causes an increase in oxidized LDL and in small dense LDL which oxidizes more easily.
In addition to increases of postprandial TG and fasting and postprandial apoB, we show for what we believe is the first time that fructose consumption increases plasma concentrations of fasting sdLDL, oxidized LDL, and postprandial RLP-C and RLP-TG in older, overweight/obese men and women, whereas glucose consumption does not.
LDL particles are more prone to oxidize depending on the type of fat it is carrying and lack of anti-oxidants it is carrying. The more unsaturated content the more oxidized it gets. That is in stark contradiction with the recommendation to reduce our intake of saturated fat.
The LDL oxidative state is elevated by increased ratio of poly/mono unsaturated fatty acids, and it is reduced by elevation of LDL-associated antioxidants such as vitamin E, beta-carotene, lycopene, and polyphenolic flavonoids.
Since about a year I focus on animal-based food and eat a high amount of butter. My vitamin E level pre-high fat diet was 11.3mg/L. The first 2 years into the diet it was 19.9 and 17.8mg/L and now since the more focused approach it is 25.3mg/L (reference values of 5 and 20).
A severe increase in saturated fat and a doubling of my vitamin E intake. I can only wonder how that has affected the level of oxidation of my LDL particles.
As you can see the overall picture is complex. As for the question “Do we know what causes atherosclerosis?”.
I think the answer is yes but science is in trouble. From what I could find, cholesterol is not the cause and that is also in line with how bad the results are in prevention. Not until research comes out that shows high levels of circulating LDL causes malfunction in VSMCs.
How can science keep up its multi-billion industry of cholesterol-lowering drugs while at the same time admitting that they were wrong about cholesterol?
We were able to ban cigarettes. We are unable to ban sugar. As long as we are not able to reduce the impact of sugar and high glucose, we’ll not be able to prevent atherosclerosis.
There are other causes than smoking and sugar but in order to be a cause, it seems first there must be a deleterious effect on the functioning of the VSMCs.
Update: In the comments there was a reference to Subottin’s work. After watching it again I realized why the thickening of the intima is taking place.
The reason why thickening of the intima takes place is to maintain blood pressure! Although people with high blood pressure are at higher risk, the problem is with localized low pressure.
The mechanism works in such a way that by increasing the thickness of the intima, pressure can be restored. So it is by design that the intima is supposed to increase in thickness but… The problem of low pressure isn’t fixed due to how we affect the flexibility of the arteries with our lifestyle so that a low pressure area persists and the thickening has to persist as well.
Previously I collected different studies to see how the mice perform on ketogenesis. Despite having a diet that often consists of >90% fat they produce disappointingly low BHB levels. Without thinking much about it I just assumed they are bad at fat metabolism biased by thinking they are typical high carb eating animals so they are less well adapted at burning fat.
But I may have been wrong about that idea.
A recent discussion and consequent article on exercise performance and the ketogenic diet brought up the hindrance of sufficient carnitine to import long chain fatty acids (LCFA) into the mitochondria at high intensity levels (>=80% VO2max). I looked for studies and found one that tested medium chain fatty acids (MCFA) versus LCFA at low and high intensities. And indeed MCFA metabolism at high intensity is not impaired. On the other hand, carnitine becomes less available at high intensity and we see a paralleled reduction in LCFA.
Back to our favorite lab animal… But we’re not talking about exercising mice!?! Indeed we are not but when I looked back at my overview page of the different studies with keto mice, I also mentioned a study that, instead of providing the usual fat, provided hydrogenated coconut oil and the mice were able to achieve BHB levels of >5mmol/L!
So this got me thinking, if they are able to produce high levels of BHB with the right type of fat then the issue must be in the import of LCFA and a reduced capacity to import them into the mitochondria. Does this mean they have an issue with carnitine availability?
We get carnitine from animal food and more so from red meat. If you had a look at the overview then you also see that the mice get a very low amount of protein, typically around 5% and occasionally only up to 10%. Could this have a limiting effect on their carnitine availability? The protein content may not be enough and then we have to see what the source of protein is because that may already be a poor source carnitine by itself.
Most of the ketogenic diet (KD) chow provides casein as a protein source so there is no naturally occurring carnitine in the diet which means the animal has to obtain it from its own production.
We may have forgotten that mice are scavengers and don’t pass on the deadly remains of other animals. They need their carnitine just as much as we do. They are not 100% herbivores.
Rodents scavenged both fresh and skeletonized remains with gray squirrels only scavenging skeletal remains. Wood mice were most active in winter and scavenged both soft tissue and bone.
Here I want to have a look at just a few studies of the many for available evidence that carnitine plays an important role in the fat metabolism of mice.
In a first study we see a 40% reduction in carnitine for mice on KD versus a regular diet.
Serum concentrations of β-oxidation intermediates carnitine and acylcarnitine were paradoxically decreased in STKD mice, indicating a possible dissociation between hepatic gene expression and serum content of oxidative markers (Fig. 6A).
In the next study in humans they supplemented healthy adults with carnitine and various conditions. These were not individuals on a KD diet. They fasted overnight and then did exercise with carnitine right before exercise. The carnitine supplementation had the strongest correlation with ketogenesis.
In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.
In the figure (a) shows a very high correlation right after exercise. (b) shows the correlation 4 hours after exercise and (c) shows the combination of a and b together with the baseline sample 1 hour before exercise.
One more study shows a much better functioning of fat metabolism in patients who are carnitine deficient after carnitine supplementation. Their side effects remind us about the KD mice. Fatty liver, higher inflammation markers etc.. When supplementing with carnitine this all improves, including insulin sensitivity.
Inflammation, glucose intolerance, hepatic steatosis and other side effects
What happens when you must eat a higher volume to get to those fewer MCFA in your diet while you can’t process the LCFA? Fat builds up. It arrives in the liver but can’t get into the mitochondria that easily so it buffers up.
Once you get fat accumulating in the liver you’ll experience insulin resistance so an OGTT will show glucose intolerance.
What doesn’t get picked up remains in circulation and goes again into fat storage. We know that increased storage of fat in the adipose causes a chronic low grade inflammation so it should not be a wonder that a KD diet in mice leads to these side effects.
So these mice are eating energy that they can’t use, naturally that also leads to weight gain which we observe in ad lib feeding.
There is of course a reason why mice need to have a low protein intake in the lab. They have a roughly 7-fold higher metabolism than humans. It results in too much gluconeogenesis from the digested amino acids and this would hinder ketogenesis.
So on one hand we need to keep the protein low to induce sufficient BHB but on the other hand we hinder their BHB production by limiting their carnitine availability.
So do mice have an impaired fat metabolism? I guess not. It looks like their diet causes them to be deficient in carnitine.
I only see a few options to correct the model and that is to increase carnitine supplementation and/or feed MCT oil. Any other type of feeding will not represent a human ketogenic diet sufficiently. Also carnitine may reduce their BHB production due go gluconeogenesis so probably the best is to put MCT oil in the diet.
What can we learn from this and apply in our human life? If you are on a ketogenic diet and want to compete in sports, it may be worthwhile to experiment with supplementation of carnitine before the race to maximize transport of the LCFA and somehow find a way to ingest MCT during the race for maximum availability of fat into the muscle mitochondria.
It is pretty obvious by now in sports is that if the body requires something then you need to give that in order to enhance performance. Be it vitamines, minerals, energy… whatever it needs to produce that wattage, make sure it doesn’t fall short to sustain the performance. Except for one element. Even though it is right there in front of our face and of all the researchers, it is overlooked…
A presentation I recently looked at summarized it all yet somehow seems to miss it.
A first thing to note is that endurance exercise such as running and cycling elicit AMPK activation. More so under a low glycogen state than under high but nonetheless the activation is there.
The reason I’m highlighting AMPK is just to give some background on what we are looking at. AMPK is responsible for setting in motion the growth of mitochondrial mass. During exercise, mitochondria get (partially) damaged. They need to be split up so that the damaged parts can get recycled and the other parts that are in good health become the seeds to multiply and grow a bigger mitochondrial mass overall.
What does this enhancement in mitochondrial mass result in? Indeed, increased exercise performance, higher ATP production.
In sports physiology they know very well that this results in a higher fat oxidation rate as the presentation further highlights.
The results below, in the presentation, are from a study looking at endurance training in a group of moderately overweight men. We see that there is no adaptation in the amount of carbohydrate oxidation but there is adaptation in the amount of fat oxidized. This is in the Trained group and the Diet group which were fed a reduced amount of calories.
The study also looked at a group to keep calories identical in order to exclude if the adaptation is due to weight loss. Also here the Trained-identical calories group shows the same adaptation in fat oxidation. C is the control group.
What this tells us is that both weight loss and endurance training stimulates a greater fat oxidation capacity with no change in carbohydrate oxidation.
I’ll speculate later on about why this is happening but let’s first have a look at what determines our level of fat oxidation, our maximum fat oxidation rate. The presentation continues on this topic…
As fasting is prolonged, the fat oxidation goes up and we see a correlation with the circulating free fatty acids (FFA).
Actually, the data shows us a very high correlation between the free fatty acids (FFA) and maximum fat oxidation.
Further evidence is given in the presentation from a study that looked at ultra-endurance. Normal diet, at least nothing specific to a ketogenic diet or high fat diet in general, yet we see again how the body adapts to increase fat oxidation.
Pointing out the obvious
So it should be clear by now that the body, as an adaptation to endurance, increases its fat oxidation capacity. On one hand by increasing mitochondrial mass and on the other hand by making more fat available in the circulation via FFA. Without more mitochondrial mass you cannot process more FFA and more mitochondrial mass is useless without additional fuel.
But what are these researchers missing? The type of fuel!
If the body wants to increase fat oxidation in order to sustain that demand in performance, wouldn’t it be natural to provide the body with that fat, which it is demanding for, during exercise?
Why is there not a single trial that involves ingesting fat in one way or another during exercise?If we want to go for a higher peak fat oxidation, shouldn’t we simply eat fat to get our FFA up?
Is it fair research when putting athletes on a high-fat diet, thereby having a higher reliance on their maximum fat oxidation rate, to supplement them with carbohydrates pre/during exercise which releases more insulin so that the insulin can stunt fat release thus lowering their circulating FFA and showing no performance gain, or worse, performance loss?
In the pre‐treatment trial, all subjects received a standardised CHO‐rich breakfast providing 2 g kg−1 CHO;
That is comparing highly optimized high-carb athletes with high-carb fueling to highly optimized high-fat athletes with stunted fueling. You might as well just put a concrete block around their legs.
A study that compared normal versus ketogenic diet in exercise monitored the FFA during the exercise. It shows how important the availability of FFA are during exercise. Being the main source of fuel and being greatly dependent on, it is only natural to supplement with fat. The mixed diet group has a much lower reliance on fat and we also see that in a much lower fluctuation during this exercise exercise.
Specifically towards the most intense part of exercise during this test we see the lowest availability of FFA. What would happen if we’re able to maintain that level of FFA from the start towards the end by ingestion or, just for the sake of experiment, infusion?
This is an area where research could see a lot of surprises and progression in understanding.
A point I did not address is the type of fat used. This is actually very important because long chain fatty acids (LCFA) require carnitine for transport into the mitochondria.
Carnitine content reduces to less than 30% during high intensity (100% VO2max)
Medium chain fatty acids (MCFA) do not require carnitine and thus are able to sustain a higher rate of appearance in mitochondria. But for that they need to be made available in circulation at a higher rate as well.
It is of course just a hypothesis but the most obvious thing would be protein sparing. Engaging in long duration activity requires energy. If it would all have to come from glucose then our body would have to break down muscle as a source for gluconeogenesis. By relying more on fat, both the energy requirement can be met and at the same time protect our muscle from catabolism.
If you want to go more in depth on this protection mechanism then you can read a few of my previous post on the subject. You’ll see it has quite broad implications.
I have received a cancer diagnose last year. Thankfully my predating interest in metabolism already exposed me to lots of research material, including about cancer. I already collected material in the event I would ever get cancer. It may seem a bit ironic but we have a high chance being faced with it in our eventual life, either personally or someone close to us. I look at it from the positive side, it gave me a head start in figuring out what to do about it .
It allowed me to put together a number of things that would, at least in theory, help cure my cancer. Now it was time to put that theory into practice.
Along came my brother in law with glioblastoma half a year later who I have guided onto the protocol with great results so far.
I want to share with you my protocol because research is advancing in the field of standards of care (SOC) which means surgery, radiation and chemo, and the combination of it with dietary therapy. Specifically the ketogenic diet is promising but why should you have to wait another 10 or 20 years before they make it part of a suggestion in therapy.
Why combining it with the ketogenic diet? Research is stil frail but positive. What I’ve seen from papers is that a very low carb diet, which the ketogenic diet is, is creating a much more favorable environment to target cancer with SOC of which all the details still need to be unraveled.
It modulates the immune system, lowers growth factors, reduces usable energy metabolites etc. Underneath the description of the protocol I go a bit deeper into the effects of each so that you can understand why they are part of it.
In the unfortunate event that you are unable to stop the cancer, the protocol will provide you a much needed reduction in side effects. That alone makes it already worth doing.
So let’s first have a look at the protocol and then the rationale of it.
Below are the elements required and we’ll see how to put them into practice.
I want to stress though, if you want this to be successful then under no circumstances deviate from it. More curcumin and more omega-3 is OK but more protein is not OK, less ketogenic is not OK. They all have a specific purpose, including the timing! Read the explanation below to be better informed about the why.
Curcumin (Theracurmin double strength)
Omega-3 oil (EPA; DHA)
Ketogenic diet – High on fat, very very low carbohydrate (<20% but preferably as close to zero as possible)
This protocol contains a ketogenic diet. It requires some adjusting for your body to get into it which may lead to some discomfort at first. In the initial phase you may loose weight through fluid clearance. This also clears some electrolytes so make sure you take up a bit more salt.
Get acquainted with the diet and the side effects during initiation. Stick through it and check around how to resolve the issues. If issues occur, they are normally very minor and generally require a little bit of adjustment and they fade away after about the second week.
Get an estimation of your body weight and fat percentage so that you know how much protein you can eat. For example, an 80kg person with 20% body fat means 80 * 20% = 16 kg of fat. 80 – 16 = 64 kg of lean mass. We simply change the kg of lean mass to gram so we get 64 gr of protein per day. This looks very little but I’ll explain further down.
The intake of protein has to be spread across the day, we’ll do that in 3 meals. Roughly 25%, 30% and 45%. It doesn’t have to be super exact but make sure the morning contains less and the evening more but don’t change it too much. 20%, 30%, 50% is still OK or 20%, 35%, 45%. So according to the example above: 25% of 64gr or 16gr protein for breakfast, 30% of 64gr or 19.2gr at lunch and 45% of 64gr or 28.8gr.
As soon as you wake up, take 4 pills of the Theracurmin double strength and 1 pill of Omega-3 supplement containing DHA. Do the same right before going to bed but now also include the melatonin (+/- 3mg).
Vitamin D3 is not shown on the schedule but I recommend to take a daily dose in the morning and/or before exercise and to start taking it as soon as possible. It takes a while before your plasma level is up so just covering the SOC period is not enough. 10 000 IU every day will likely be needed. This may seem as a lot initially but you have to understand that vitamin D3 supports your immune system and your immune system will be consuming vitamin D3. It is important to keep the level up. Personally I want to reach around 80 mg/dL of 25(OH)D to make sure I hit the maximum out of the linear dose reponse that it brings.
As you can see from the graph, it takes 4 months to reach the plateau of +/- 80 mg/dL with a daily dosage of 10 000 IU (250 microgr).
MCT oil must be taken regularly throughout the day. I’ve mentioned 8 times on the schedule. You can vary to more times but I would not recommend less than 5 times. You can, for example, make a blend called bulletproof coffee which is the MCT mixed with coffee, butter (real butter!) and coconut oil. Be creative, take it however you want but take as much as possible and regularly throughout the day.
Breakfast, lunch and diner are high fat, ketogenic meals, preferably zero carb but at least very very low carb. How high in fat? As much as you can comfortably eat to feel full. If you are still hungry after a meal or if you are losing weight, increase fat intake. You will not get fat from the fat. More than likely you will be losing weight. Even if you would gain, you can sort that out after getting cured from cancer!
There is no snacking between the meals. You will not be hungry anyway but (bad) habits can be strong. No sugary drinks at all, no fruit, no nuts & seeds, no low-carb candy bar etc… We aim for zero carb during the whole day and limit dietary intake to those 3 meals.
Do your best to leave 4 hours between diner and going to bed. The more hours in between the better. But aim for at least 4 hours.
The protocol should be applied at least across the duration of SOC. The ketogenic diet however is recommended for the rest of your life. It is one thing to get cured from cancer but you need to prevent recurrence as well.
The good thing is that, perhaps apart from rare genetic issues, this protocol is safe to apply for long duration. So if the tumor is receding but not so fast, you can continue applying the protocol for a longer period. The diet itself is covered by a lot of research, showing improvements in health. For example it is used to treat epilepsy and reverse Type 2 Diabetes. In general it will make you a healthier person.
I was diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma. I had the luxury to try out my protocol without SOC because it was a slow growing tumor. I wanted to know its strength, a first try-out of the theory. Note that I was about 2.5 years on very low carb at the moment of diagnosis, have applied the full protocol without SOC for about 1 month and after the protocol I remained very low carb.
Now 1 year later, there is no change in size. No regression but also no worsening. It is possible that my case proves itself rather difficult to cure with the protocol alone because it is located in lymph glands with cancerous b-cells. Cells that are themselves part of the immune system and designed to clear cancerous cells.
I have started radiation therapy and we’ll see how that works out in a couple of months.
My brother in law was diagnosed with glioblastoma with a high % chance of recurrence within 5 years. The standard protocol was applied. First surgical removal of the tumor followed by radiotherapy combined with chemotherapy. The periods of standard treatment, apart from the surgery, were every time fully covered by my protocol.
The first image is before surgery showing the tumor on the back side of the brain on the left.
The following picture is the result after surgery.
The protocol was started shortly before radiotherapy and chemotherapy, which lasted for 1.5 months. He was essentially symptom free from the treatment. It was so remarkable that he was interviewed because of it.
The MRI after 3 months, shown below, is encouraging. No relapse so far.
The treatment is not finished yet. There are 6 rounds of 1 full week of heavy chemo whereby he follows the protocol starting 1 week before and covering the week of the chemo. Throughout the rest of the period he remains close to very low carb but not fully.
We’ll have to wait for the next 5 years to see how successful we have been but in the mean time another scan was done, 6 months post surgery, with a doctor who was very enthusiastic about the result. Still nothing came back so far. Crossing fingers.
The beauty of this treatment is that it targets the energy source of cancer, it targets the uptake mechanism of the energy and actively works on the growth mechanism without negatively affecting healthy cells. Secondary, it also helps activate immune cells promoting the detection and clearance of cancer cells. In addition it can even work to augment the effectiveness of certain chemo drugs like temozolomide (1) (2) .
Sounds too good to be true? It isn’t but it is also no miracle cure by itself. Cancer is a though beast to handle. The cancer cells live in a tumor micro-environment which needs to be destroyed as well. The protocol is a potent adjuvant to SOC.
PS: The references below are just there as a first hint if you want to look into it more deeply. I didn’t provide a reference for every statement but in case you want to delve into it deeper, I’ve mentioned the molecules involved so it should be relatively easy to come up with the research.
Curcumin has been widely studies, also in combination with cancer treatment. It shows great potential and while its effects are via multiple mechanisms, perhaps the most important one is PI3K inhibition in cancer cells. However, raising insulin very potently increases PI3K activation and destroys the effect that curcumin has on PI3K, therefore it is vital to keep insulin low. That is why the first meal should be zero carb but also very low in protein, to let curcumin work while insulin is low. This is also the reason why I recommend 4 hours between dinner and bedtime with curcumin so that insulin is low enough for curcumin to do its work during the night without being hindered by insulin.
Plain curcumin powder will not work !!! The absorption is very bad and we need to get a high enough dosage into the cancer cells. The reason I recommend Theracurmin is because this has shown to be the highest bio-available form. I am not affiliated with them and will not hesitate to recommend a different brand if I find another one that has a higher bio-availability. However, my experience is with this brand and dosage.
“Curcumin Inhibits Joint Contracture through PTEN Demethylation and Targeting PI3K/Akt/mTOR Pathway in Myofibroblasts from Human Joint Capsule” – Ze Zhuang, Dongjie Yu, Zheng Chen, Dezhao Liu, Guohui Yuan, Ni Yirong, Linlin Sun, Yuangao Liu, Ronghan He, and Kun Wang – 2019 – https://www.hindawi.com/journals/ecam/2019/4301238/
“Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway.” – Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, Yang D, Yang A, Yu Y- 2018 – https://www.ncbi.nlm.nih.gov/pubmed/29328421
One specific feature of the fatty acid DHA is that it needs to have its place in the cell membrane. By taking it as a supplement we increase our intake and chances for it to end up in the cell membrane. This is very crucial because DHA has been shown to prevent the conversion from PIP2 to PIP3. PI3K triggers the conversion of PIP2 to PIP3 and from there AKT gets activated which in turn stimulates mTORC1 resulting in growth. Omega-6 oils displace DHA in the cell membrane so we want to avoid omega-6 (seed oils).
“Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells” – Zhennan Gu, Jiansheng Wu, Shihua Wang, Janel Suburu, Haiqin Chen, Michael J. Thomas, Lihong Shi, Iris J. Edwards, Isabelle M. Berquin, and Yong Q. Chen – 2013 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765042/
Melatonin has many synergistic effects with the keto diet and curcumin. They all enhance fat metabolism, forcing cells to adapt to it or die if they cannot. Furthermore it is able to destabilize HIF-1a and inhibit AKT expression and phosphorylation (activation). Both important factors in the growth of cells.
We have an opportunity to make the effect of curcumin stronger by combining it with melatonin. I have only found 1 example but I don’t see a reason, for now, to think that the effect would only be limited to this case. Of course further studies will have to validate against other forms of cancer.
AKT and mTORC1 and mTORC2 (driven by PI3K) all 3 target NF-kB which further drives growth transcription. So it is great to see that the combination of curcumin and melatonin together have a higher potency to stop NF-kB.
“Melatonin potentiates the antitumor effect of curcumin by inhibiting IKKβ/NF-κB/COX-2 signaling pathway” – Sandeep Shrestha, Jiabin Zhu, Qi Wang, Xiaohui Du, Fen Liu, Jianing Jiang, Jing Song, Jinshan Xing, Dongdong Sun, Qingjuan Hou, Yulin Peng, Jun Zhao, Xiuzhen Sun, and Xishuang Song – 2017 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592853/
Melatonin’s actions don’t stop there! It actually forces cancer cells to reduce glycolysis in the cytosol by increasing the uptake of pyruvate in the mitochondria. It lowers the lactate production and fast ATP production that are normally the result of glycolysis.
Melatonin also helps to scavenge electrons in the electron transport chain that didn’t flow through it correctly and would otherwise create reactive oxygen species (ROS). It is so important, melatonin even increases endogenous antioxidant production. SOD2 activity is increased via SIRT3 on which melatonin has an enhancing effect.
Melatonin uptake into cells is thought to be through GLUT1. It likely competes with glucose for uptake into cells of which the result is a lower uptake of glucose.
“Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer.” – Hevia D, González-Menéndez P, Quiros-González I, Miar A, Rodríguez-García A, Tan DX, Reiter RJ, Mayo JC, Sainz RM – 2015 – https://www.ncbi.nlm.nih.gov/pubmed/25612238
Furthermore, there is interaction between glucose, insulin and melatonin. Taking melatonin supplement has the ability to lower insulin and glucose secretion providing additional power to curcumin in its fight against PI3K.
It inhibits gluconeogenesis in the liver and increases glucose uptake in skeletal muscle and adipose tissue helping to reduce glucose availability to cancer cells.
“Melatonin Uptake by Cells: An Answer to Its Relationship with Glucose?” – Mayo JC, Aguado A, Cernuda-Cernuda R, Álvarez-Artime A, Cepas V, Quirós-González I, Hevia D, Sáinz RM – 2018 – https://www.ncbi.nlm.nih.gov/pubmed/30103453
The effects of vitamin D on the immune system are very important. When the immune cells need to be activated, they’ll increase their expression of vitamin D receptors to take in vitamin D. The vitamin supports differentiation of cells which cancer cells have trouble with and works against metastasis and works anti-proliferation.
Many research results show positive effect of endogenous ketone production while undergoing cancer treatment. This is clear in petri dish, mice and rat studies and also in human studies and has been shown to slow and even stop progression.
Getting the ketone production high enough suppresses glucose output from the liver. This lowers substrate availability for the cancer cells. A ketogenic diet also keeps insulin very low which is needed for curcumin to be effective.
Cancer cachexia is in part serving as a source of glucose. A ketogenic diet will oppose skeletal muscle breakdown preventing or slowing down cachexia.
All inflammatory markers go down on a ketogenic diet. This is important as the cancer treatment (radiation/chemo) will cause higher levels of inflammation putting a burden on your body. This inflammation will raise triglyceride levels giving cancer cells the building blocks to proliferate.
A very important extra is that it also helps stimulate the activation of T-cells and NK-cells through better oxygenation of the tumor microenvironment. BHB also helps T-cells to build up a better glycogen reserve to have a better burst growth in case of pathogens. Being treated with radiation and/or chemo will affect your immune system making you more vulnerable for disease so you need this re-enforcement.
One of the main reasons normal cells are protected is because they are able to adapt to the high fat diet. Cancer cells have a problem with this. Melatonin, ketones and curcumin all optimize fat metabolism essentially shifting the environment into one that is detrimental for cancer.
“Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury.” – Miyauchi T, Uchida Y, Kadono K, Hirao H, Kawasoe J, Watanabe T, Ueda S, Okajima H, Terajima H, Uemoto S – 2019 – https://www.ncbi.nlm.nih.gov/pubmed/31196960
The MCT oil is very easily converted to ketones. Together with the bulletproof coffee and the ketogenic diet, we’ll be able to stimulate a high enough level of beta-hydroxybutyrate (BHB). The butter, cream and coffee itself all either deliver fats that can be easily converted to BHB or, in case of the caffeine, it stimulates fat release which also helps raise BHB. If you can measure your blood level of BHB then we want to aim for above 1 mmol. Higher is better but let’s say don’t let it get much higher than 5~6 mmol measuring fasted in the morning.
So MCT and the bulletproof coffee essentially help the ketogenic diet to raise BHB.
Meat and fish are high in proteins. These proteins, when eaten, are broken down into amino acids. A number of these amino acids serve as a signal in the body to stimulate growth via insulin secretion but also directly, sensed in the cell via mTOR. While there is nothing wrong with growth in itself, during cancer treatment we want to avoid any stimulation of growth as it is overstimulated in cancer cells.
We want to be able to kill the cancer cells at a higher rate then the growth of new cancer cells. Otherwise the tumor can never shrink. When insulin is raised, even only modestly by protein intake then insulin is raised across the whole body, also in the cancer cells.
We can’t afford not to eat protein but taking in protein together with fat causes a reduced speed of absorption with a lowered peak activation of insulin so being on a high fat diet will greatly help to reduce the insulinogenic impact.
Below are some pictures from my brother-in-law. He jumped from one day to the next on this diet and was able to adapt within the guidelines. This is to give you an idea of what to eat. There are plenty of resources on the internet but some are not always so strict on carbs because they don’t have cancer in mind.
It basically comes down to a wide variety of vegetables and a source of animal protein such as fish, chicken, pork, beef etc.. mixed in with a lot of fat. When I say a lot of fat, I literally mean 70% and upwards of your total caloric intake. Fat is your friend.
A small note on the vegetables. Some are high in carbohydrates and are therefore completely excluded such as any type of potato and legumes. Other vegetables such as carrots and parsnip are relatively high. They can be put on the plate but in lower quantities. Keep in mind, we do not want to stimulate insulin with protein but neither with carbohydrates.
Especially the combination of carbohydrates with protein is very potent at stimulating insulin. This is very bad and to be avoided at all cost.
The protocol can be overwhelming at first but once you’ve settled in it is actually not that big of a deal. Once you are comfortable with it you can always step it up a notch. Below are a few topics which deserve attention and can be applied when physical energy permits, when the mental state allows for it. They can be applied at a delayed stage as well but I recommend to start as early as possible and maintain it as long as possible, without forcing yourself! No stress, if you don’t feel like it then don’t. I do find them worth to consider.
Not oxygen supply but acute oxygen deprivation will help stimulate the body to adapt to a low oxygen state. Hypoxia actually stimulates autophagy (which insulin prevents). There are breathing exercises that will create acute hypoxia to which the body will react by creating more capillaries and increase hematocrit and hemoglobin so that more oxygen can be carried and distributed within the body. Follow the link or search on my page for “breathing” and you’ll find an exercise I have composed to get you started. It was posted in December 2019.
Together with curcumin, ketogenic diet and melatonin, being active moves the whole body into the same optimization for fat metabolism. Aerobic activity helps to get adapted and keep those muscles insulin sensitive and receptive to glucose. In the event that glucose and/or insulin would rise, we need the skeletal muscles there to buffer as much as possible.
A tumor is also dependent on lactate. By performing aerobic activity you stimulate the circulation of plasma, possibly helping to clear the lactate from the tumor environment. Lactate suppresses immune function and is involved in spreading (metastasis) of the cancer and is converted to useful metabolites by other cells and shared again with cancer cells.
Don’t overdo the exercise though. Making it too intense also puts a burden on your immune system. Keep it light to moderate, minimum 30 minutes and preferably around an hour every day. The heart rate should go up but you shouldn’t loose your breath while talking.
Similar to exercise we can make sure glucose is taken up by brown and white fat and our skeletal muscles through cold exposure. The cells will try to generate heat using glucose increasing their uptake and consumption. There are 2 common ways to do this and that is taking cold showers and/or taking ice baths. The level of exposure that is needed is not always clear, this for both duration and temperature. I have adopted a habit of always taking cold showers.
The immune system and building muscle requires a lot of zinc so my basic recommendation would be to monitor zinc status and make sure you are not low. Aim for being at least in the middle of the reference range but don’t stress over it. Take a zinc supplement if needed. Increasing your vitamin D level will also increase the absorption rate of zinc.
Inonotus obliquus (Chaga mushroom)
All interventions are aimed at enhancing fat metabolism and shifting away from glucose metabolism together with lowering glucose availability.
Chaga has been researched and shows potent anti-cancer abilities. Its action is also targeted to enhance fat metabolism.
“Continuous intake of the Chaga mushroom (Inonotus obliquus) aqueous extract suppresses cancer progression and maintains body temperature in mice” – Satoru Arata, Jun Watanabe, Masako Maeda, Masato Yamamoto, Hideto Matsuhashi, Mamiko Mochizuki, Nobuyuki Kagami, Kazuho Honda, and Masahiro Inagaki – 2016 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946216/
With all these extras you now have a range of additional tools to use in case you have the energy and feel you can take up an extra arsenal of cancer suppressing adjuvants.
I want to keep this section light but informative enough so you can think about how to prevent getting cancer in the first place.
I would describe cancer as a state of forced growth. This is because a lot of the hallmarks of cancer, the so called oncogenes, deformed mitochondria, lactate production etc… are all normal (!) for a growing cell. It doesn’t make it cancer. What makes it cancer, to my view, is that it can’t get out of this growth state.
So how do we get into this state? There are many causal factors of which genetic mutation can be one of them but it is unlikely to be the only causal factor apart from some rare cases. Detrimental genetic mutations are on the rare side.
Consider it like fire, you need a fuel, a heat source (for example a spark) and oxygen. None of them alone cause fire but we all think of fuel as THE single component that causes it.
For cancer, you preferably need a low oxygen environment (fructose will do just fine!), you need a growth stimulating environment (high carb -> insulin, check). You can add a higher omega-6 (seed oils) to push away the protective effect of DHA and you now have… the standard American diet (SAD) diet.. as a good basis to increase your risk. SAD but true.
Now it is just a matter of time under this highly inflammatory state to get the right (epi)genetic change that will push a cell over the edge to become locked into this growth state. It almost universally results in an augmented expression of PI3K (stimulate growth) and/or PTEN (suppresses growth) ablation hence the protocol targets PI3K. PTEN is there to control PI3K so both an over-activation of PI3K or reduction in PTEN activity can set you on the path to cancer. This over-activation or suppression both can come from a genetic modification but this modification results from a disturbed metabolism.
There are 2 fields of thought which is the genetics origin and the metabolism origin as causes for cancer. Analogous to the fire, both have a role to play. Without the genetic mutation you don’t get a lock-in in growth but without the disturbed metabolism you can’t create the genetic mutation that easily (unless for those rare cases).
The book of David Sinclair was helpful in this because he explained that our cells have a mechanism that supports either growth or repair but can’t do both. By stimulating growth which insulin does powerfully, you don’t give the cell time to do repair of damage, particularly to the DNA.
The damage is caused by the growth so that’s why there is always a swing needed from growth to repair and back. This cycle comes automatically from feeding and not feeding but under conditions of high insulin and lack of oxygen we end up in a state continuously stimulating growth or at least a state where we can’t get sufficient DNA repair done. At some point the right strings (DNA mutations) are touched and lock the cell in growth permanently.
Now restoring sufficient oxygen is not going to help us out anymore and low insulin is also not going to be sufficient to resolve the cancer cell but the above described protocol targets everything possible to kill this growth and resolve the cancer.
If you found this information useful, if you managed to improve your outcome or your loved one using this information, please consider a donation to show your appreciation.
Why a theory behind obesity? Isn’t it just CICO? I’ll use a simple analogy.
You find a little puddle of water so you start mopping it up but then it comes back so you do some more mopping. The puddle of water keeps coming back and bigger if you don’t do any mopping so people tell you to do more mopping and faster. You’re not doing enough to get rid of the puddle!
But if you would look at the root cause, a leaking tap, then you know you have to fix the tap and then clean up the puddle with a last mopping.
CICO is the mopping and my theory shows you how to fix the tap.
First we will have a look where the name HyProCICO comes from which sums up the whole theory in a quick easy name.
To make the information digestible I’ll first describe the theory and then go into the details to provide the backing for the theory.
I will also have a Testing section that shows some scenarios where I simply explain the findings based on my theory. Here and there supported by some reference material.
But before we get into that final Testing chapter there is first a section on the different types of leaking taps that can lead to obesity.
So the sections are:
The name that I have given to the theory refers to the hypothalamusthat does the sensing of energy and amino acids to satisfy energy needs and protect the protein in the body from being used for energy. It will do this by regulating simultaneously both Caloric Intake and Caloric Output.
You’ll find that the theory is actually quite straightforward and doesn’t require much explaining but the ongoing debate in the (scientific) dietary communities shows this root cause is somehow missing from their view.
It will not be a complete theory. It doesn’t cover all regulation that takes place. I’m primarily looking at the most important components in relation to obesity. The hypothalamus is a central organ in this theory but this organ does so much more than the aspects touched here.
There are 2 main aspects that drive food intake. A first is the requirement for energy and a second is driven by the need for sufficient amino acids.
The brain – energy
The brain is a highly energy hungry organ. It senses how much energy is circulating in the blood via the hypothalamus. Energy includes more than just glucose. Since the brain can also run on beta-hydroxybutyrate (BHB) it measures or responds at least to the energy level through the totality of glucose and BHB but possibly also fatty acids.
The totality of energy may be the driver to stimulate hunger… However, it is possible that the level of glucose itself will drive control over what energy is freed up.
When the glucose level becomes inadequate, insulin must lower and glucagon must increase to enable the freeing of fat and conversion into ketones. The hypothalamus controls these hormones through the nervous system.
The brain – amino acids
Not only energy is required in sufficient quantity. Protein requirements also need to be met within the body to make sure cells can be maintained, misfolded or damaged protein can be cleared etc. both for the brain and the rest of the body.
As such the hypothalamus senses circulating amino acids and will stimulate feeding behavior when levels go down.
The energy sources
What happens if there is not enough energy? From the hypothalamus, nerve signals and hormones are secreted to regulate energy release from within the body storage, energy consumption by the body and external energy intake into the body.
We keep a fairly steady temperature production but it can be turned down a notch to save energy. Some people feel the urge to move or exercise a lot or can’t sit still while others don’t budge. Reducing the urge to move can also help preserve energy.
The theory will not go into the aspects of increasing or reducing energy expenditure although the regulation of it is part of why obesity establishes itself. I will briefly reference to these aspects under “The details – Energy Control”.
The amino acid sources
Amino acids become available through our diet by eating protein or are partially coming from recycled proteins within our body. Some of the amino acids will be lost into gluconeogenesis (GNG), no matter their source.
If levels drop below a certain threshold then feeding must be stimulated.
What if we can’t find food? What if on top of that our energy reserves are low (liver glycogen, stored fat)? As a last resort, our protein mass (skin, skeletal muscle, organs) will be broken down to continue providing energy to the brain. This is a situation that must be prevented. We have both an energy level to protect as well as an amino acid level. The brain needs both to function.
So on one hand we have the energy need of the brain that must be met and on the other hand we have the protection of protein.
If the brain senses low energy it will stimulate hunger. If the energy level is not restored, it will break down protein for energy.
The detected low energy level points out that we don’t have much reserve left so the brain better starts stimulating hunger to avoid being starved itself.
In a similar way we find that amino acids dropping in level will stimulate hunger.
What this means is that we have 2 components that both must be available in sufficient levels. We may have sufficient energy but if amino acids are low, we’ll still be stimulated to eat. Vice versa our amino acids level can be sufficient but energy may be low, also stimulating us to eat.
When there is a low level of energy sensed, the GNG process will be stimulated helping to convert circulating amino acids to glucose so low energy can lead to low amino acids. This is an important aspect when looking into obesity. It also helps explain loss of protein mass while still having sufficient fat mass when the sensing goes awkward.
So much for the theory, let’s now have a look at the science behind all of it.
A paper released just recently has found neurons that stimulate glucagon or inhibit glucagon release based upon the glucose level sensed.
In our high-carb diet based society there is little research into the role of ketones and generally only considered as a negative element such as in diabetic ketoacidosis. Therefor we get statements like the following:
during energy deficit such as fasting specific hypothalamic glucose sensing neurons become sensitized to decreased glucose
Become sensitized to decreased glucose or equally satisfied with ketones as with glucose?
What I do suspect but cannot verify is that the stimulation of hunger must be dependent on the total energy but that the level of glucose specifically creates a shift to more lipolysis when its level is going down. I could not find any papers that have looked at this specific aspect.
What we can be certain about is that the brain doesn’t just look at glucose. It can also detect the level of fatty acids and ketones. The capillaries in the hypothalamus region are more ‘leaky’. Presumably to have a better and faster sensing of actual circulating levels.
There is indirect evidence that shows ketones could be part of sensing the totality in energy. Research shows us a reduction in ghrelin when administering ketone esters. But ketones could also have a different, more direct or modulating effect on ghrelin production. Either way, BHB contributes to signaling that energy is available.
Central administration of leucine has also been used and shown to activate hypothalamic mTOR leading to a reduction in feeding. Interesting is that leptine also stimulates mTOR in these same cells explaining the reduction in feeding behavior from leptin.
The hypothalamus can also activate the adrenals to release cytokines which will help increase lipolysis in the adipocytes.
I’ll let the next paper speak for itself:
The arcuate nucleus (ARC) of the hypothalamus contains at least two crucial populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in energy demand. Neurons making pro-opiomelanocortin (POMC) decrease food intake and increase energy expenditure through activation of G protein-coupled melanocortin receptors (MCR) via the release of a-melanocyte-stimulating hormone (aMSH). Until recently, the prevailing idea was that the neighboring neurons expressing the orexigenic neuropeptides, agouti-related protein (AgRP) and neuropeptide Y (NPY) (NPY/AgRP neurons) increased feeding and decrease energy expenditure primarily by opposing the anorexigenic/catabolic actions of the POMC through both the competitive inhibition of melanocortin tone at the postsynaptic level and via directed inhibition of POMC firing rate (Fig. 1)
You see here how energy shortage is reacted on by increasing feeding and decrease energy expenditure and energy abundance lowers food intake and increases energy expenditure.
Now you can understand why weight loss strategies that reduce food intake and demand increase in energy expenditure through activity are completely contradictory to how the body wants to regulates itself ! We think it is all about the energy we eat while it is about the energy that the brain senses. Feeding and decreasing energy expenditure belong to each other, satiety and increased energy expenditure belong to each other.
The following picture is created to show the role of leptin but it gives a good overview of the hypothalamus and several of its structural elements. Mainly the tanycytes which are the sensors, their presence close to the fenestrated capillaries and how tanycytes affects NPY and POMC.
In a mouse test they injected BHB to make it directly available to the hypothalamus but they noted an increase in feeding behavior. That goes against my theory because we’re injecting even more energy than what already circulates so if anything they should be less hungry.
This is a good case of why research leads to wrong conclusions and thus creates confusion. Luckily though, they investigated thoroughly and even confirmed in their discussion that there was a downregulation of glucose AND MCT transporters in the blood-brain-barrier (through which BHB can get into the brain). With lower energy sensed by the hypothalamus due to lowered glucose and BHB you stimulate feeding behavior. Just like the theory predicts.
It would be interesting to find out why such injection has lead to reduction in MCT.
Ghrelin is a hormone secreted in the stomach and said to induce hunger. Research shows us that it depends on NPY and AgRP which are secreted by the hypothalamus. At least one of these 2 elements is needed for ghrelin’s effect.
Ghrelin is highest before a meal and lowest after. As such it is a hormone that signals digestion of food. By signaling that there is nothing in the digestion, through raising ghrelin levels, it gives the hypothalamus a sense that there is no incoming energy or amino acids. And this also means that there is room to stimulate dietary intake.
A mouse knockout model of the ghrelin receptor in the hypothalamus leads to increase in energy expenditure and ablation of obesity. This simulates a signal that food is being digested thus energy and amino acids will be coming in so it increases energy expenditure.
The theory shows a mechanism in which there is a well balanced sensing and regulation. As long as the total energy is OK and amino acids are OK then there is no issue.
When it comes to energy, in order to stimulate hunger and create a surplus in body weight, we must have a chronic situation where there is sufficient energy available but 1) the energy in the circulation is ‘under representing’ what is available OR 2) there is a problem in the sensing or representation of the circulating energy in the hypothalamus.
For various reasons it is possible that energy is not released sufficiently so there is a reduced level of energy in the blood circulation.
The sensing is a never-ending process depending on the continuous passage of blood. Any reduction or increase in blood flow can drive less or more energy to the hypothalamus. Any issue in processing that energy level in the hypothalamus cells will lead to a wrong correction.
When the sensing detects low energy, it will stimulate feeding. No matter how much energy is available in storage.
When it comes to amino acids, a low sensed level can lead to a surplus intake if the dietary protein are low while the energetic value of the food is high. Food with low protein content will not be able to raise the circulating amino acid levels enough so more food needs to be eaten to come up with a sufficient level of amino acids.
A paper from Kevin Hall indicates this by having compared ultra-processed food with unprocessed food. Free intake of food resulted in a perfect match of protein intake (490 kcal/d) between the 2 groups. With energy sufficiently available, it was the protein that drove the intake in this study.
So what are some of the various cases apart from protein dilution in the meal?
I’ve already covered the detrimental roles that fructose play in health and pointed out its link with obesity but let’s focus in on its specific action on the hypothalamus.
As highlighted earlier, the signaling works through the activation of mTOR for which sufficient ATP needs to be available. Glucose, BHB, fatty acid all ensures sufficient ATP. Fructose however depletes the ATP in the cells when it gets metabolized. That will lead to activation of AMPK which is kind of the opposite of mTOR.
The reduction of ATP causes a signal of reduced energy availability. The body responds by increasing hunger and lowering energy expenditure.
Fructose can be taken up from the diet but it can also be produced endogenously. When fructose is metabolized, it leads to an increase uric acid. Uric acid itself activates aldose reductase which is responsible for converting glucose to fructose so fructose has a positive feedback loop whereby fructose ingestion and metabolism further increases fructose production and metabolism.
Insulin is also involved in the energy signaling and regulation by the hypothalamus. Insulin is a known activator of mTOR so it will stimulate the sense of energy excess leading to satiety and energy expenditure. The cells in the hypothalamus express insulin receptors. It is possible that the metabolism of fructose within these same hypothalamus cells creates a similar insulin resistance as happens in the liver.
Pointing out further the effect of fructose metabolism, when fructose is absorbed in liquid form and in high enough quantity and frequently, it will lead to insulin resistance causing high secretion of insulin for prolonged time. This appearance of insulin resistance can be seen as an indication that fructose is metabolized in the body and is thus able to reach the brain where its metabolic effect is indicated above.
As we saw before under fructose, ATP depletion caused activation of AMPK. 2DG, by hindering glucose metabolism in the hypothalamus also causes a reduction in ATP with a resulting increase in AMPK, stimulating an increase in glucagon and corticosterones.
The long term usage of antidepressants is associated with weight gain. When I bumped into this I first wanted to check if they are feeling more hungry. And indeed, it is even used as a combo in underweight elderly to handle their depression and weight at the same time.
So could there be any influence of antidepressants on the glucose sensing in the hypothalamus? It turns out that the drug citalopram, an SSRI antidepressant, reduces the blood flow in the hypothalamus.
Do we find citalopram associated with weight gain?
Celexa (citalopram) has been associated with slight weight gain, but it’s thought that the drug itself doesn’t cause this effect. Rather, the weight increase is likely due to improved appetite from taking the drug. A better appetite can cause you to eat more, leading to increased body weight.
Because I remember from hearsay that lack of sleep can cause weight gain I thought this would be interesting to check out. The story is more complex here because it is specific to sleep and temperature regulation is important since we can’t simply put on an extra cover when we are cold.
A study in rats does show melatonin induces a reduction in blood flow in all areas including in the hypothalamus. But is it representative for humans?
Such a brain wide reduction in blood flow would also result in a reduction of oxygen supply. In addition it also lowers energy signaling from all other hormones such as leptin, ghrelin, insulin etc.. Interesting…
Melatonin is produced during the whole night and during our sleep the body temperature drops. How is this temperature regulated at night?
During our sleep, temperature is diverted from the core to the skin through vasodilation. This probably evolved in our evolution that way to protect us from too cold ambient temperatures with death or frost bite from cold during sleep.
We find that melatonin increases BAT and beige activity which are known to create heat by uncoupled metabolism which means consuming energy just for the sake of producing warmth. It is possible that melatonin acts directly on the fat cells so it doesn’t work through the hypothalamus.
This is perfect to keep warm during the night and would explain the reduction in brain blood flow to simulate energy shortage, thereby releasing more energy which then can be used for the heat generation.
The hypothalamus can also induce thermogenesis but this is part of energy expenditure and falls under sensing sufficient energy and is also stimulated by cold sensation signals (like a cold shower).
The level to which our temperature can drop will make a difference in how much energy needs to be spent to keep us warm.
What we see in obese subjects, a high energy evening meal causes less weight reduction versus an isocaloric daily intake where the largest portion is taken during the morning.
I’m trying to look at a diverse list of scenarios to see if I can explain the outcome using the theory. In such a way you’ll be able to understand how I see the model working and allows you to refute or ask questions. My theory does need validation.
Glycogen Storage Disease type III (GSD3)
A first example is GSD3 where they report a prevalence of enlarged liver (hepatomegaly) of 98%. This disease has a problem with breaking down glycogen into glucose to release it into the circulation. It also shows us that there is not really a fixed ceiling for storing glucose in the liver. The liver adapts growing larger to store more.
The patients are intolerant to fasting. They can generate ketones but their glucose levels are too low (because they cannot free it up fast enough from the liver) despite the ketones they may produce.
One of their symptoms is (chronic) hunger. With their reduced available glucose, it could be beneficial if they are on a high fat diet to generate more ketones and as such provide the necessary circulating energy.
Linked to GSD3 but actually the opposite we find in Inuits. They have a mutation that reduces their ketone production capacity. Where GSD3 cannot provide enough glucose, we find in the Inuits affected by this mutation that they cannot provide sufficient ketones.
Not only does the high protein allows them to maintain glucose level but in addition is the fat helping them with keeping warm in the arctic climate.
I couldn’t find any clear references but traditional eskimos are said to have enlarged livers and eat a high level of protein. If this is correct, it would fit the theory in such a way that there must be an increased capacity to produce glucose for a longer period of time throughout fasting in compensation for a reduced ketones production capacity.
If anyone can contribute to finding good references towards the protein intake and the liver size then I would be very grateful.
Their traditional food does seem to provide a large amount of protein. I see numbers around 133~166gr of protein for adult males (20-60y) while they have an average height of around 165 cm. That would support a high protein consumption.
A study tested the effects of hunger, appetite and weight loss in 2 different groups. A first group on a low carb high protein diet (30%p; 4%c; 66%f) and another group on a medium carb high protein diet (30%p; 35%c; 35%f). They were fed ad libitum. To understand the results make sure you have also read my article on gluconeogenesis being a supply driven process.
What happens here is that the high protein intake helps to replenish the glucose level in the liver for both groups. The difference however is that the low carb group has lower meal-triggered insulin release. This allows the low carb group to release more fat for energy which leads to ketone production.
The medium carb group has a very high insulin secretion due to being combined with high protein. This is how incretins work out (check out the video under “Regulation”). This raises the excursions into hypoglycemia post absorption. In such a phase the hypothalamus may react with hunger stimulation.
Both low ghrelin and high leptin should signal to the hypothalamus that there is abundance of energy so it should lead to a reduction in appetite and increase energy expenditure.
Active research in this field has defined the term leptin resistance. One of the mechanisms could be that leptin has a reduced capability to cross the blood brain barrier (BBB) and as such cannot provide its signaling. This has been shown in mice by leptin administration directly in the brain, bypassing the BBB. What causes this issue in crossing the BBB is under investigation. There are also thoughts regarding disturbed signaling because the hypothalamus could get inflammed when metabolising fructose due to the stress of low ATP availability.
When it comes to ghrelin, it is probably a non-factor. Meaning that high ghrelin can induce hunger but it does not mean that low ghrelin induces satiety nor that high ghrelin is needed to induce hunger. Activation of AMPK is already sufficient to release NPY so although low ghrelin may signal digestion is going on, if AMPK is activated for some reason then hunger is stimulated.
Obese insulin sensitive and obese insulin resistant
There are obese people who develop insulin resistance as you would expect from high fructose consumption. Yet there are also those who remain sensitive.
I’m missing quite some data on these people but in the following study something caught my eye. The obese sensitive people have significant lower fasting triglycerides. What this may mean is that the fat which is produced in the liver from fructose is quicker cleared and moved out of the liver. This would prevent NAFLD and insulin resistance.
They may have a quicker response to the fructose induced lowering of insulin and increase in glucagon. By quicker releasing the fat from the liver there is less chance of building it up to cause restance.
The fat however is created and needs to be stored elsewhere.
The development of a fetus during a period with inadequate maternal protein consumption has consequences for the offspring. This has been tested in Sprague-Dawley rats. What is interesting about this experiment is that the offspring rats had an increase in hunger, consuming more calories, yet at a lower body weight which the authors suspect is due to increased energy expenditure. This is a very big difference in energy expenditure. It is not eat more and weigh the same, but eat more and weigh less.
Qasem RJ, Li J, Tang HM, Pontiggia L, D’mello AP. Maternal protein restriction during pregnancy and lactation alters central leptin signalling, increases food intake, and decreases bone mass in 1 year old rat offspring. Clin Exp Pharmacol Physiol. 2016;43(4):494‐502. doi:10.1111/1440-1681.12545 https://pubmed.ncbi.nlm.nih.gov/26763577/
So what is going on? The following study gives us a glimps of what may have taken place. They looked at hypothalamic cells in the fetus of maternally protein restricted rats. Most of the upregulated genes are involved in the mitochondrial complex. I suspect this is not only in the hypothalamus but system wide and is done to increase mitochondrial mass with the purpose of increasing the protein protection by enhancing fatty acid metabolism.
Frapin M, Guignard S, Meistermann D, et al. Maternal Protein Restriction in Rats Alters the Expression of Genes Involved in Mitochondrial Metabolism and Epitranscriptomics in Fetal Hypothalamus. Nutrients. 2020;12(5):E1464. Published 2020 May 19. doi:10.3390/nu12051464 https://pubmed.ncbi.nlm.nih.gov/32438566/
Further changes noted in the offsprings is an enhanced gluconeogenesis capability. Improving the ability of the liver to increase glycogen storage and maintain glucose output is another way to protect protein from serving as a glucose substrate.
A very recent study, also from Kevin Hall, comparing high carb with low carb ad lib intake shows again the need to meet sufficient amino acid levels. This time however there was not an equal intake of dietary protein so what happened?
The previous study from Hall (see “Obesity”) had a different distribution in macronutrients. Here the much higher carb offers more protection from protein catabolism by providing a large amount of glucose and stimulation of insulin. Insulin protects the muscle from breakdown and the high glucose makes sure the liver can supply a steady stream of glucose to satisfy the needs of the brain.
OK but why did the low carb diet led to such a high intake? By taking out carbs from the diet, the liver glycogen lowers. This lowers glucose availability. The brain will react by lowering insulin and increasing glucagon. This will lead to a higher level of GNG whereby also the circulating amino acids are converted to glucose.
BHB can compensate for the lower glucose but the production of BHB is not immediately increased. To cover this transition until BHB production is high enough, protein need to fill in as a source of energy (glucose) so there is a temporary need to increase protein intake to help supply the circulating glucose and circulating amino acids.
The body does not want to give up its own protein so it will increase hunger feeling. This will lead to an increase in food intake whereby the food intake will directly cover the glucose requirements. The food contains little carbs so the protein in the food will for a part be converted to glucose while at the same time the dietary protein also have to serve as a supply to maintain amino acid levels.
In the first week we see an immediate jump up in dietary intake. During the first days BHB production is too low to help compensate for the drop in glucose. As BHB ramps up throughout the week we see the intake reduce. In the second week we see a marked lower intake versus the first week now that BHB has reached a meaningful level.
There is still a difference in caloric intake because the protein in the diet are not sufficient to keep the circulating amino acids up. GNG is high for the low carb diet and there is very little glucose from the diet. A longer study is required to see how this further evolves. This study has helped us view what happens during the first 2 weeks when transitioning into a low carb diet.
Preprint reference: “A plant-based, low-fat diet decreases ad libitum energy intake compared to an animal-based, ketogenic diet: An inpatient randomized controlled trial” https://osf.io/preprints/nutrixiv/rdjfb/
Once the transition period is over, it will be easier for the body to obtain energy from BHB through fat metabolism and glucose through the GNG process. There is a system wide adaptation whereby the brain will start making ketones, the skeletal muscle will use more fat for energy etc..
The whole system has to adapt to rearrange how it provides sufficient energy to the brain and thereby finds a new equilibrium to spare amino acids.
To further support the “transition period” with more evidence, the following study shows a longer trial of 30 days whereby we see an accelerating fat loss after 15 days. It was also conducted by Kevin Hall et all.
It was also noted that there was increase urinary nitrogen. As I explained, the lack of sufficient compensation by BHB during the transition will result in the breakdown of protein.
Urinary nitrogen excretion increased by 1.5 ± 0.4 g/d (Table 3; P = 0.0008) during the KD phase and indicated significantly increased protein utilization. The time course of the changes in urinary nitrogen excretion showed that the increased protein utilization occurred within the first week of the KD and persisted until day 11 (not shown).
Further support for the transition effect comes from a study where they tested the low carb effects of exercise across a very short duration. Via phenylalanine they found a greater oxidation of the amino acid showing that if you are not sufficiently transitioned, low liver glycogen will result in low glucose and therefor a greater amino acid conversion to glucose via GNG.
In an experiment to overfeed people we see that calories do matter to gain weight. But what the referenced study did was gradually increase overfeeding (20%, 40%, 60%) with each time a period of ad lib food intake to satiety. In the ad lib period after the 60%, the subjects naturally started to eat less calories than at baseline.
None of their allowed drinks contained any liquid sugar or fructose allowing for the automatic regulation of energy intake and expenditure.
Finally the authors conclude:
regulation must be dominated by hypothalamic modulation of energy intake. This result supports present conclusions from genetic studies in which all known causes of human obesity are related to defects in the regulation of appetite.
Siervo M, Frühbeck G, Dixon A, et al. Efficiency of autoregulatory homeostatic responses to imposed caloric excess in lean men [published correction appears in Am J Physiol Endocrinol Metab. 2008 Apr;294(4):E808]. Am J Physiol Endocrinol Metab. 2008;294(2):E416‐E424. doi:10.1152/ajpendo.00573.2007 https://pubmed.ncbi.nlm.nih.gov/18042669/
Migraine (added 1 dec 2020)
Today (1 dec 2020) I bumped against a post on Twitter explaining why you can get hungry when you have a migraine. Because of this theory I immediately suspected an impact on hypothalamic blood flow so a great case to test the theory.
As it turns out, this year a paper came out showing a reduction in blood flow in the hypothalamus. It perfectly demonstrates how the hypothalamus is the central organ that detects energy and responds accordingly.
Why the blood flow decreases is unfortunately not revealed.
Our results reflect that immediately prior to a migraine headache, resting regional cerebral blood flow decreases in the lateral hypothalamus. In addition, resting functional connectivity strength decreased between the lateral hypothalamus and important regions of the pain processing pathway, such as the midbrain periaqueductal gray, dorsal pons, rostral ventromedial medulla and cingulate cortex, only during this critical period before a migraine headache.
There was a study done in rats to find out the effect of lauric acid, a medium-chain fatty acid. They wanted to study the anti-obesogenic properties of lauric acid. They noticed a modulation of NPY and AGRP in the hypothalamus showing there is a reduction in hunger stimulation.
The mRNA expression levels of the anorexic neuropeptide POMC in the hypothalamus between the LT group and the other groups were not different, while the gene expression levels of the orexigenic neuropeptides NPY and AGRP decreased significantly in the LT group.
The hypothalamus, based on what it detects will control the vagus nerve to control the pancreas in releasing glucagon and insulin. The following experiment shows that when stimulating the vagus nerve, it will lead to a higher metabolism and more weight loss in an isocaloric setting.
This drug is injected and successfully treats diabetes and causes weight loss. What does it do? It’s a GLP-1 receptor agonist, basically it mimicks GLP-1 that is normally released as food comes in and tells us that we have eaten enough.
We see that it reduces the response to highly desirable food so the mental desire for food is influenced by physical factors with signals passing through the hypothalamus.
“GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial” https://pubmed.ncbi.nlm.nih.gov/26831302/
How it achieves the increase in weight reduction is through increasing metabolism by stimulating T4 secretion.
The evidence is now quite broad but let me add one final element. Central administration of bile acid in the brain, presumably signaling incoming food and more specifically fat, signals energy and is responded to by stimulating the sympathetic nervous system. This increases the metabolic rate through various ways leading to reduced weight accumulation, up to weight loss itself.
Pot-smoking and gastric bypass versus gastrectomy (Added September 2021)
The hypothalamus has a receptor for endocannabinoids (CB1). Both surgical methods to reduce the amount of food intake are met with different effects on resting metabolic rate because of a difference in endocannabinoid levels. Low levels of cannabinoids stimulate energy expenditure via brown fat activation while higher levels reduce it. This brown fat activation is triggered via sympathetic nervous stimulation, done by the hypothalamus.
This same receptor CB1 is responsible for the effect of feeling hungry when smoking cannabis.
Cannabis also affects the secretion of gut hormone GLP-1, leading to a lower insulin response. That insulin response is directly affected by GLP-1 levels but the hypothalamus also responds to GLP-1 as we have seen earlier under liraglutide.
As you can see, the hypothalamus is central to the regulation and it acts based upon all the different inputs that tell us something about the energetic status of the whole body.
I hope it is clear with this article that obesity is not simply a matter of calories. Yes a calorie is a calorie and under controlled equal caloric feeding you may not gain weight but such controlled feeding is not our natural world. However, there are even rodent lab models that you can even give a lower caloric content while still gaining weight versus healthy controls.
When people get obese, we need to think in terms of energy and amino acid sensing. It’s the sensing that needs to be fixed, not how much we actually have available. We have no long lasting will power over this sensing, we can fight it but eventually succumb to the automated regulation.
When the brain signals hunger and lowers metabolism… eating less and moving more is completely opposite of what the body wants to achieve and only further aggravates the signal if we don’t fix the underlaying problem.
We need to work with the system, not against it:
Protect your protein by having a sufficient supply of circulating amino acids
Avoid any other issue outlined above that would interfere with the correct sensing of energy or would interfere with releasing sufficient energy from the storage places
Take care of these problems and the body will auto-regulate itself towards a more lean and active individual.
For most people, taking out liquid fructose (and alcohol) and sugar in general will solve much of the problem so consider this number 1 on the priority list.
Note: No doubt that there are other causes that can lead to obesity but they likely will all show somehow to influence the described mechanism and may not always be fixable when they cannot be adapted for by lifestyle changes.
I won’t know until I have antigen testing done but I’m fairly sure I was infected with the SARS-COV-v2 aka COVID-19 at the starting of March. Last year I was also diagnosed with lymphoma. The connection between the 2 is that the lymphatic system is involved in the defense against infectious pathogens. If you have cancer in your lymph nodes then viruses become a potential aggravating factor. This is something I experienced as the affected lymph nodes became more sensitive during the COVID-19 infection and on the latest PET-scan showed increased activity. Naturally my interest is sparked in this area.
So with that introduction, the main reason to write about vitamin D is because of its role in the immune function and because that is of interest to the general public. For me there is an extra motivation due to the lymphoma. So join me in the exploration and let’s see what we can dig up.
The research is split up into observational, interventions and cellular studies so that we can have a better overview and see how they relate to each other.
Vitamin D is an enhancer in reactions and helps to either upscale or downscale effects. It affects the expression of over 2000 genes.
In the “Structure” section you’ll see about the half life of the different molecules and at the bottom section you’ll see about supplementation. This makes research tricky if it is not followed up and measured properly. The way the dosing is done can already create no noticeable effect so I won’t be looking into those kind of studies.
If you already know the ins and outs of vitamin D then you can skip the next section but I want to introduce high level the different forms and at the end I’ll show what I consider good supplementation strategies and why. If you don’t do it right, you could be throwing money in the toilet (or donate it to me to keep this site up and running 😉 ).
As most people know, vitamin D3(D3) is produced in the skin through UVB exposure. There is also vitamin D2 but I’ll not get into that. D3 is cholecalciferol and is what you find in most supplements. It has a half life of around 24 hours or even a bit shorter.
D3 is converted in the liver to 25-hydroxyvitamin D which I’ll refer to as 25D from now on. This is what is measured in your blood panel by your doctor and it is also known as calcifediol or calcidiol. It has a half life of several weeks. You will see that in most of the scientific literature, this is what is reported on and measured to find association with clinical outcomes etc..
25D is not yet the active form though. It needs to be further converted to 1,25 dihydroxycholecalciferol(1,25D) also known as calcitriol. This is done by both the kidneys and virtually every cell in your body. Its half life is in the range of a few hours at most.
Important about observational data is that we look at 25D status before disease appears. If 25D is affected by a disease itself then it doesn’t make sense to claim any links on the diseased state due to 25D status.
First too give some idea about blood levels of 25D, a level of 20 ng/mL (x2.5 -> 50 nmol/L) is reported to be adequate by this paper to prevent respiratory infections. Whether this is correct is another question but it allows you to map your own 25D level to this reference.
When looking at athletes, measuring 25D before and after and record their incidences of illness and severity symptoms related to respiratory infections during winter. They also measured cathelicidin which we’ll come back to under the “Mechanisms” section. At the start the median 25D (total so including the small fraction of D2) was 57 nmol/L and at the end, after 4 months, dropped to 47 nmol/L. The groups were divided as follows:
12-30 nmol/L (deficient) -> 4.8-12 ng/mL
30-50 nmol/L (inadequate) -> 12-20 ng/mL
50-120 nmol/L (adequate) -> 20-48 ng/mL
>120 nmol/L (optimal) -> >48 ng/mL
Everything tracks along their 25D status according to nr of infections, severity and duration.
I want to highlight from this study the following 2 graphs because they relate to the ‘cytokine storm‘ that has been mentioned so much in relation to the severity of symptoms during a COVID-19 infection. They took blood samples and tested the cytokine reactions in the lab.
As you can see, those with sufficient vitamin D levels are able to produce more cytokines. Keep this in mind when reading further below the “Immune cells” section.
The next study did a similar thing except they measured 25D every month and had respiratory infections evaluated by the investigators. The investigators were blinded from the 25D status. Again we see a correlation in incidence, severity and duration based on 25D status. The researchers also conclude that levels of 38ng/mL or above should be maintained.
There were only 18 subjects >= 38 ng/mL so the sample is relatively small compared to the 180 who were below. Note though that the 18 subjects were the ones who still had a high 25D status at the end of the study. At the beginning there were 32 people. So at the end of those 18, 83.3% in the high 25D group survived the observation period without infection compared to 55% in the low 25D group.
One more follow up study this time in Canadian children shows us again the same observation. They found 25D status to be correlated with respiratory infection (and age). Levels of <70 nmol/L (28 ng/mL) increased the risk with 50% and levels <50 nmol/L (20 ng/mL)increased the risk with 70%.
For interventions we can look at what the effect is of supplementation (either supplementation or increased sun exposure) and how that prevents disease but we can also look at a diseased state and see if supplementation helps you recover more quickly. It is very well possible that only one of these scenario’s is effective. We’ll see.
A major review finds a reduction in death when D3 is administered together with calcium. That is interesting but is that due to improvement in immune function and thus prevention from infection-caused death or more due to reduction in fracture etc.. so no conclusions from this one yet.
The task would be too big but you would have to go through all the trials in the review and see what dosage was used and how frequently administered. Not only intake but you’d also have to assess to what levels the subjects their 25D was improved. There is a lot of variation and that influences the reported results.
A first RCT shows quicker recovery when supplementing with 25D. Interesting as usually D3 is supplemented. This is probably done to overcome issues with the liver in the conversion of D3 to 25D. Both the duration and the severity were reduced with a supplementation of 10 microgram/day (400 IU/d). Because it was double-blind placebo controlled, we don’t know by how much this raised patients’ 25D levels. They did report that about 59% started with a deficiency of levels below 30 ng/mL.
The next intervention was in school children (6-15 y) and noticed a reduction in Influenza infections versus the placebo group. They were given 1200 IU/d and the trial was run from December to March. Although a reduction is noted, we have no clue on their starting and ending 25D status.
In a special group of patients with frequent respiratory infections or antibody deficiency they gave 4000 IU/d for 1 year. Their baseline level of 25D was around 50 nmol/L (20ng/mL). The daily intake resulted in an increase towards 133 nmol/L (53,2 ng/mL). They went into the details to detect differences in bacteria and fungi and found primarily Staphylococcus aureus and fungi to be reduced. The end result is a reduction in infection burden as we see throughout all the studies.
As a third category we can see what we find in the lab. What do we find as effect at cellular level and does that fit within our observations and interventions?
For the actual mechanisms we’ll need to look at the active form 1,25D.
The active form 1,25D keeps the epitehlial cells and endothelial cells better clustered together, decreasing permeability so keeping a tight junction. We see this reflected in the blood-brain-barrier and also in the gut.
In the gut they tested the effect using lipopolysaccharides (LPS). LPS causes an increase in gut permeability allowing pathogens, from which the LPS originates, to enter the body. We see here a fight between LPS trying to downregulate the vitamin D receptors (VDR) while 1,25D restores it.
“1,25-Dihydroxyvitamin D3 preserves intestinal epithelial barrier function from TNF-α induced injury via suppression of NF-kB p65 mediated MLCK-P-MLC signaling pathway.” https://europepmc.org/article/med/25838204
Both the D3 supplementation and production in the skin from the sun causes the skin to produce cathelicidin. This is like our endogenous antibiotics production but the effects are more wide and modulate our immune system as shown in the image. For more information you can check the reference but I wanted to highlight specifically the antimicrobial function.
First a quick word of explanation. What we have seen with COVID-19 is that the immune response is prolonged in the more severe cases. The so called “cytokine storm” is a severe and prolonged response of the immune cells which are tasked to destroy infected cells. In the lungs, the endothelial cells are the first in line to be infected and destroyed by the immune cells but that leads to leakage of plasma into the aeveoli, restricting the ability to breath.
What we want is an immune system that can respond quickly by very fast proliferation so that enough immune cells are created to handle the infected cells but also fast to stop the virus from spreading and infecting many cells. This is the defense that is needed. We also want a quick turn-down of this proliferation once the threat has been handled to avoid excessive damage.
If the initial response is not fast and strong enough, we risk a more prolonged fight because the virus is able to spread more, causing a prolonged increase in immune cells and destruction of infected cells increasing the overall damage.
A first good indication of modulation by vitamin D is the presence of a receptor for it. 2 review paper shows us that the immune cells (monocytes, macrophages, dendritic cells (DCs), T-lymphocytes and B-lymphocytes) have VDR’s to produce their own 1,25D showing that vitamin D is an active player in these cells.
In order to replicate fast, the immune cells require ATP via the cytosolic glycolysis. This happens in T-cells when an anti-gen is presented. Glycolysis means that the ATP has to come from glucose.
Unfortunately I could not find tests on immune cells but we can have a look at cancer cells and embrionic cells, which both are cells that proliferate at a rapid rate, to have an idea what 1,25D may mean. We see in a cancer-specific cell line that the active 1,25D is able to reduce glycolysis. In an embryonic kidney cell line it is able to modulate the reductive state. I’m interpreting here but what it means, according to my insight, is that it will support the capability to switch back from glycolysis to oxygen phosphorilation. This is important for a cell to stop the proliferation.
Not only can it help to induce differentiation, it can also help to prevent differentiation. This is an example of how 1,25D provides a supportive modulatory role. In the paper below, the preventive action improves encephalomyelitis, an autoimmune disorder potentially linked to T17 cells.
One of the reasons vitamin D could be improving autoimmune diseases is because it modulates dendritic cells (DCs) in such a way that it reduces T cell response. DCs are the cells that present antigens to T cells who then respond to this antigen by fast proliferation.
This effect on DCs seems contrary to the fast and strong (but short) response needed from the immune system but what I suspect is going on is that it doesn’t disable DCs ability overall but is probably fine tuning DCs more towards pathogens somehow.
We find improvement in immune function with higher 25D levels so it must have a beneficial effect somehow.
Although not directly about vitamin D, I found a presentation that talks about how incorrect adaptation in metabolism of the T cells can lead to several diseases.
Taken together, it shows that vitamin D is important in potentiating a correct adaptation in immune cell metabolism to provide the right type of response.
The cell cultures reveal interesting modulatory roles primarily in the differentiation, possibly by regulating the way energy is metabolised. The papers show the highly complex world of immunology.
Not only is there direct effect in the way immune cells behave but also in the protective barriers such as the epithelial lining in the gut and vasculature do we see its involvement together with an antibiotic production.
The observation and intervention sections show us, in line with the cell cultures that vitamin D status, measured through 25D, does make a difference and is important to maintain an optimal state. What that level should be is debated but it is clear that there is no upper limit defined as of which there are no more positive effects observed.
There is toxicity possible but for that you need to go higher than what you would receive from the sun. Our skin darkens in response to sun exposure and this lowers the D3 production but with supplementation we don’t have this automatic protection. But we are talking about regular intake of 500 000 IU for a longer period whereby the toxic effects are easily reversed by stopping the supplementation.
The exercise has been done reviewing the dosage used and timings. The best approach seems to be on a daily basis. The reason for that is because you are normally supplementing with D3 which has a half life of 24 hours roughly. This means that if you take a big bolus once a month of say 100 000 IU, the next day your body has 50 000 IU left, the day after 25 000 IU etc.. After 7 days you have about 1562 IU left. In contrast if you take 2000 IU every day then you only get 60 000 IU per month but it will be much more effective.
This is also reflected in a review of randomized control trials regarding respiratory infections:
There is evidence that daily administration is more effective than high-dose bolus administration [OR = 0.48 (95 % CI 0.30–0.77) vs. OR = 0.87 (95 % CI 0.67–1.14)]
Personally I decided to take multiple dosages of 1 000 IU spread across the day. Whatever the dosage you take, I would suggest to spread it from early morning to late afternoon. This is 1) to anticipate on the liver conversion capacity of D3 to 25D and 2) to avoid any negative effect on sleep.
I would suggest not to take D3 in the evening. I could not find any papers showing an immediate influence on melatonin production but out of precaution I think it is better to mimick the natural production we would have from the sun. A light dose in the morning, the heaviest dose at noon when the sun is the highest and a light dose again in late afternoon.
There are papers that looked at 25D and sleep and find correlation between bad sleep and 25D deficiency. There is also a paper looking at MS patients reporting reduction in sleep. However they looked at metabolites in urine rather than sleep or direct melatonin production so we can’t really derive much from those results. Due to the long life I don’t consider 25D having an immediate effect related to intake and melatonin.
Anecdotes and even a very thorough n=1 experiment indicate it is best not taken at night. My way of intake likely will be synergistic with the circadian rhythm.
If I know I will exercise then I’ll take an extra dose. It has been shown that exercise increases 25D production during and post exercise. I suspect that this is due to the increase in blood flow pushing more D3 through the liver. Whatever the cause, we want our 25D status up so this is a good way to make most use of your D3 intake (or sunshine).
I came across a couple of resources and started to appreciate how different fructose is from glucose. In the low carb community, carbohydrates are obviously avoided or at least high amounts of it as they are generally considered bad. I support this approach but when we zoom in on fructose we notice that it is not so much glucose that is causing all typical chronic diseases but fructose.
Sugar is associated with metabolic syndrome (hypertension, insulin resistance, Type 2 Diabetes, NAFLD, cancer, …) as well as brain-related issues such as Alzheimer’s, dementia, Parkinson etc.. but what is it about sugar that makes us succumb to disease? Being half glucose half fructose, there are only 2 components to look into.
Can it really be glucose? We do have populations that have been eating high amounts of rice, wheat, potatoes… products that are all high in starch which get broken down into glucose and absorbed into our body. Yet metabolic syndrome is something that started to appear and evolved since the 1900’s.
What I will show you here is how fructose is causal to a lot of these diseases so that you understand it is fructose specifically that needs to be kept out of the diet. I do not recommend high starchy foods (glucose) either due to other factors but that is not the focus of this article.
Immediately some people will reflect on fruit because that is what we usually associate with fructose. The danger from fructose comes from a combination of quantity and speed so there is less to worry about as most fruit comes in a package of fiber that needs to be munched down so that speed and quantity is low. However, if you take down for example 3 or 4 oranges in one go then you’re no better off than drinking a glass of sugar sweetened beverage (SSB).
As a starter I would advice to listen to the Attia podcast with Rick Johnson, M.D. , researcher of fructose since many years. The podcast is packed with knowledge, it has opened my mind on fructose. I’ve used it to find research papers to support the link with the diseases I’m listing below.
Insulin Resistance (IR)
A first topic I already covered in another article where I explain about the differences in Insulin Resistance based on fructose versus low carb. It comes down to fructose metabolism causing a buildup of diacylglycerol or DAG. The effect of it is that it prevents insulin signaling.
To show you that the effect of fructose is real and already known since a long time. The paper below tested a hypocaloric diet with different liquid forms (glucose, galactose and fructose) in 14 days. They discuss other papers where they have seen every time that hypocaloric diets increase the insulin receptor in different cell types. This is an effect attributed to the hypocaloric content. What they noted was that in case of fructose there was no such increase in insulin receptors.
Closely linked to IR we have NAFLD. The accumulating fat from the fructose metabolism in the liver causes IR but if it further aggravates then it develops into NAFLD.
There is a specific mechanism activated in response to the high fructose availability and that is carbohydrate response element–binding protein (ChREBP). This mechanism increases cholesterol synthesis but it also stimulates de novo lipogenesis. That is unfortunate because it is the buildup of fat that is causing the problems so creating more fat is the last thing needed.
I suspect that fructose has a similar profile to glucose to stimulate ChREBP. This is how excess in glucose is handled. There is a second pathway via SREBP1c but this is insulin mediated. ChREBP downregulates SREBP2 yet in how far that is different from SREBP1 is unknown to me at the moment. It is possible that with IR already build up, insulin won’t be able to activate SREBP1 much.
What is important here is that when de novo lipogenesis is activated, it also converts glucose to fat. So not only does fructose get turned into fat in the liver, it also stimulates the conversion of glucose to fat in the liver.
Glucose and fructose have differential effect on the brain apart from the regions where there is overlap. What is interesting to see is that fructose causes a reduction in blood flow in the region that is affected by Alzheimer’sdisease.
Hippocampal atrophy is part of Alzheimer’s disease. What does fructose do in a mouse study? Likely as a result of the reduced blood flow it could cause hypoxia and of course the hypoperfusion leading to insufficient nutrition with atrophy as a consequence.
Fructose consumption reduced the levels of the neuronal nuclear protein NeuN, Myelin Basic Protein, and the axonal growth-associated protein 43, concomitant with a decline in hippocampal weight.
There are different mechanisms proposed to how fructose affects the regulation of appetite. It doesn’t mean that there is only one correct. It could very well be that all the different mechanisms are at play at the same time. I won’t go into detail listing all the possibilities but you can scan through the papers if you want to know more.
What is clear from the different research papers is that fructose causes increased food intake while glucose has a satiating effect.
One of the ways obesity is stimulated is by having a high response of insulin which suppresses plasma glucose below baseline resulting in a sense of hunger. Fructose exaggerates the insulin response to glucose so that it will lead to a suppression of glucose below baseline.
How can fructose lead to hypertension? It is clear that animals respond badly to fructose.
Animal studies have shown that high-fructose diets up-regulate sodium and chloride transporters, resulting in a state of salt overload that increases blood pressure. Excess fructose has also been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the sympathetic nervous system.
But not only animals respond bad to it. After reviewing the NHANES data and adjusting for many confounders they found fructose independently associated in US adults without (!!) a history of hypertension. Blood pressure was reviewed in adults who were not diagnosed with hypertension before the study started.
After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of ≥74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of ≥135/85, ≥140/90, and ≥160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.
Also here we see a different effect and again not a good one. I’ll just directly quote from the article abstract.
In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle–triglyceride and –cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
It shouldn’t be a surprise to see here that insulin sensitivity went down and visceral fat went up. This was covered in the sections above.
So we have an increase in small dense LDL, oxidized LDL and triglycerides. There are communities of researchers who think less of LDL as a marker for atherosclerosis but I think you’ll find almost nobody who doesn’t agree on small dense LDL, (excessively) oxidized LDL and high triglycerides as dangerous markers for increased heart disease.
A study on rats shows how the damage builds up with fructose.
Under light microscopy, the kidneys of the HFD group revealed amyloid deposits in Kimmelstiel-Wilson-like nodules and the walls of the large caliber blood vessels, early-stage atherosclerosis with visible ruptures and scarring, hydropic change (vacuolar degeneration) in the epithelial cells covering the proximal tubules, and increased eosinophilia in the distant tubules when compared to the control group.
One of the causes for kidney failure is the increase in uric acid which is also a cause for kidney stones. The consumption of fructose has a fast response in uric acid production as you can see in the image under (A), the plasma uric acid. The 2 lines at the bottom are the 2 controls.
This study is in rats but for now there is no reason to suspect a differential effect in humans. What happens here is that fructose causes a lower serum level of 1,25(OH)2D3. This is the active form of vitamin D. The result is that the serum level of calcium doesn’t increase while it was expected and does take place under glucose instead of fructose feeding.
The volume of papers on the effects of fructose that I referenced above are just a small sample of what you can find. The links with the diseases are strong but is our health policy targeting avoidance of fructose? No.
It is just a guess but I think policy makers and their advisors don’t want fructose to be demonized because it is part of ‘healthy’ fruit.
I don’t want to demonize fruit either. It causes no harm when it is part of a meal or under small amounts such as in berries but I don’t consider fruit necessary.
Fruit not necessary? What about the anti-oxidants, vitamines etc.. I hear you ask. Join me for a minute in my imagination where I get dropped in a European wood far from civilization and I have to survive in the vast area, allowed to eat all the fruit I can find.
First of all, I won’t find fruit unless I’m there at the right time of the year. How necessary can it have been in our evolution?
Secondly, when I do find fruit wild in nature, it are berries. Not the monstrous sized apples etc. We cultivated them to be huge. We didn’t go through evolution with access to large fruits, perhaps apart from a few exceptions. At least not in Europe.
Thirdly, when I do succeed to find a source of berries, I’ll be in competition with the rest of the animals who all want to obtain some fructose. They also enjoy the sweet taste.
Fourthly, when I manage to find that source of berries, they are not all ripe at the same time. The 1 or 2 handful that I’ll be able to get the first time will result in about maximum a handful for the next set of days.
If you are lucky you’ll find a berry field at the right time and score some more but the point is that we cannot expect to have evolved on fruit being an important part of our diet because we simply didn’t have access to sufficient quantities for them to make a difference.
Even if it provided us a little edge on survival, today we have no need to build up a fat reserve using fructose to survive winter. Certainly not in the quantities it is consumed today. And we consume a lot through sugar which is half fructose half glucose.
The problem is most apparent when drinking fructose-containing liquids (fruit juice, sugar sweetened beverages).
If I can recommend only one thing for people to improve their health then it is to avoid sugar in their diet. The most important to cut out are those fruit juices and sugar sweetened beverages. If you can or as a second phase, cut out sugar entirely from your diet.
You’ll significantly reduce your risk of all the above mentioned diseases.