Metabolism on a ketogenic diet

Let me first clarify that this article is about a true ketogenic diet, meaning you actually produce higher levels of BHB. Why am I saying this? Because I notice quite a number of people who leave out most carbs but they don’t necessarily reach the ketogenic state due to various reasons. I’ve always said and will keep on repeating: Measure your blood BHB level to validate if you are in a ketogenic state.

That said, what is this article about? I had this idea for a while where I suspect that there is a reduction of metabolism on a ketogenic diet. This is noted by a drop in the thyroid hormone T3 and a rise in reverse T3 (inactive T3). Yet we notice a higher energy consumption which tells us that metabolism is higher. We also notice a higher heat production on a ketogenic diet. So the question is if this increase in heat production is of such magnitude that it covers both the increase versus a standard diet and the reduction in metabolism versus a standard diet.

This is not proportional, just for illustration purposes. Note though that scientifically it will be argued that heat production is part of the metabolism. I would argue it is part of energy loss but it is nor part of cell metabolism in the sense that it doesn’t contribute to metabolism. Rather it is a result of metabolism just like we produce water and CO2 which gets dissipated from our body.

The efficiency of the metabolism will determine how much heat is produced versus how much workable energy for the cell is produced in the form of ATP.

What I want to do next is look at evidence that shows if there is a lower metabolism yet a higher heat production but also at the numbers to get an estimation of how much more heat could be produced.

Before getting into the details, here is an article from Stephen Phinney, PhD (a highly respected low carb researcher) who argues for increased sensitivity to T3 because metabolism is maintained while recognizing the drop in T3. However I do not agree to this sensitivity hypothesis because as stated, I believe metabolism does go down yet the heat production goes up so that total energy consumption is maintained or even elevated.

So to recap…

  • Energy consumption is equal or increases
  • Energy production (metabolism; ATP production) decreases
  • Heat production (energy loss) increases

Lower T3

Phinney referred to unpublished data from Volek showing in a calorie restricted setting (estimated weight maintenance – 500 kcal) a drop from 4.2pmol/L to 3.5pmol/L, low-fat to KD for 14 overweight men. That is 17% lower.

“Comparison of energy-restricted very low-carbohydrate and low-fat diets on weight loss and body composition in overweight men and women” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC538279/

A second reference that he provided shows an iso-caloric comparison of 85%, 44% and 2% carbohydrates for 6 men during 11 days. The T3 levels measured were 1.78, 1.71 and 1.33 nmol/L. The 2% carb is 23% lower in T3 than the 44% carbs.

“Isocaloric carbohydrate deprivation induces protein catabolism despite a low T3-syndrome in healthy men” https://pubmed.ncbi.nlm.nih.gov/11167929/

1nmol = 1000 pmol so I think there is a mistake in units used. In any case, this second study already gives us an important indication. It seems that the level of carbohydrates in the diet determines the level of T3. Still, it could also be depending on the protein. Despite that this is kept equal in the diet, the drop in carbohydrates allows glucagon to be more active resulting in more gluconeogenesis which also catabolizes amino acids into glucose thus resulting in a lowering of the plasma amino acids.

The study noted an increase in urinary nitrogen excretion (10.91; 12.79; 15.89 g/24h). A 24% increase in protein catabolism. Please do note that switching to a ketogenic diet takes roughly 11 days for the body to adapt in order to reduce the protein catabolism. Search for “transition” on that page.

Insulin stimulates muscle protein synthesis (under sufficient leucine). By drastically lowering insulin this would make (muscle) protein more prone to catabolism unless there are counter measures. Lowering metabolism via T3 reduction, besides protection from BHB and growth hormone, is an essential element to reduce amino acid requirements in a cell that wants to build protein.

“Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways” https://pubmed.ncbi.nlm.nih.gov/16717100/

“Effect of T3-induced hyperthyroidism on mitochondrial and cytoplasmic protein synthesis rates in oxidative and glycolytic tissues in rats” https://journals.physiology.org/doi/full/10.1152/ajpendo.00397.2006

“T3 increases mitochondrial ATP production in oxidative muscle despite increased expression of UCP2 and -3” https://journals.physiology.org/doi/full/10.1152/ajpendo.2001.280.5.E761

We see that hypothyroidism results in a reduction of amino acid efflux from skeletal muscle and a reduction in protein synthesis in various tissues.

Amino acid release (alanine, glycine, tyrosine, glutamine) is increased in hyperthyroid skeletal muscle [9] while it is decreased in hypothyroidism [9, 15, 22].

in hypothyroidism hepatic synthesis of intracellular or secretory proteins is reduced by 20% and 50%, respectively [18, 40].

Total cellular protein toss during a starvation period is reduced by 50% in the hypothyroid state, mainly due to a decrease in the cytosolic compartment, while in hyperthyroidism there is no change [44]. In starvation, mobilization of hepatic proteins is decreased in the thyroid deficient state, providing a prolonged conservation [44]

source: “Thyroid hormone action on intermediary metabolism. Part III. Protein metabolism in hyper- and hypothyroidism” https://pubmed.ncbi.nlm.nih.gov/6231411/

What we have seen here is that T3 modulates (increase/decrease) the basal level of ATP production and mTORC1 stimulation affecting amino acid utilization for protein synthesis and replacement.

Circulating amino acids are measured and accordingly the body responds. Stimulate synthesis when there is abundance, conserve when there is shortage.

The ketone molecule BHB reduces protein catabolism but before we get to this point we first have to generate BHB and for that dietary protein has to be low enough in the first place. Note: I’m not saying “low” but “low enough”.

A study in healthy subjects where they put them on a 4-day ketogenic diet report what we have already seen. A drop in T3, rise in reverse T3. Interestingly they also looked at the amino acids. The gluconeogenic amino acids alanine, glutamine, glycine, serine and threonine were reduced by 8-34% while those of the branched chain amino acids increased by more than 50%.

“Hormonal and metabolic changes induced by an isocaloric isoproteinic ketogenic diet in healthy subjects” https://pubmed.ncbi.nlm.nih.gov/6761185/

An important note, circulating levels are always the result of production rate and consumption rate.

Increased UCP

UCP allows for the loss of electrons that dissipate as heat during metabolism. A higher level of UCP will mean that more heat will be generated and less ATP.

In the following rat study they gave a control diet, control+sucrose drink, low protein-high carb or low protein-high fat diet. The authors concluded the following:

Brown adipose tissue protein content and thermogenic capacity (assessed from purine nucleotide binding to isolated mitochondria) were greater than control values in sucrose-fed and protein-deficient animals, and the greatest levels of activity were seen in low protein–fed rats with a high fat intake.

Why greater in the high fat versus the high carb? Because dietary carbs result in a direct feed of glucose to the brain so there is more protection from catabolism due to the higher insulin stimulation. Dietary fat doesn’t stimulate insulin as much and in contrast requires the dissociation of the fatty acids from the glycerol backbone so that the glycerol can serve as a gluconeogenic source. But what to do with that abundance of free fatty acids? Get rid of them via thermogenesis. With a low protein-high fat diet you need a higher level of fat metabolism to get to an equal level of protection from amino acid catabolism.

The thermic effect seems to be double that from the control group.

The acute thermogenic response (% rise in oxygen consumption) to a standard balanced-nutrient meal was higher (12%) in sucrose-supplemented and in low protein groups (15-16%) than in control rats (8%).

“Influence of Carbohydrate and Fat Intake on Diet-Induced Thermogenesis and Brown Fat Activity in Rats Fed Low Protein Diets” https://academic.oup.com/jn/article-abstract/117/10/1721/4780321?redirectedFrom=fulltext

The next animal study gave the rats a ketogenic diet with 9% protein. Versus the control group they ate the same amount of calories, had reduced weight gain and generated 11% more heat. The 66% calorie restricted group had obtained a similar fat mass and lean mass composition but without the heat production.

Fig. 1.
Fig. 2.

“A high-fat, ketogenic diet induces a unique metabolic state in mice” https://journals.physiology.org/doi/full/10.1152/ajpendo.00717.2006

I do want to warn about animal studies though and caution with interpretation. 2 main issues could influence the results.

  • 1) isocaloric feeding: if a low protein diet requires more fat burning then the ad lib feeding could result in a higher dietary intake. By giving the same calories as the control diet you reduce the protein catabolism protection. This may lead to a lower thermogenesis capacity than they would do naturally and at the same time have a reduction in growth.
source: “Isoenergetic Feeding of Low Carbohydrate-High Fat Diets Does Not Increase Brown Adipose Tissue Thermogenic Capacity in Rats” https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038997
  • 2) Too low protein: when feeding animals very low protein amounts or even absent protein, they will have a lower protein assembly capacity. In order to increase heat production, fat needs to be metabolized via an increase in UCP expression and at the same time the machinery for fat metabolism needs to be enhanced. This means proteins (carnitine) need to be assembled to form the necessary enzymes, hormones etc. If the level of circulating amino acids go too low then those protein assemblies could be under pressure as well.

When evaluating this in humans we see a similar result. Energy expenditure goes up when carbohydrates are exchanged for fat while keeping protein equal. The subjects on low carb had a TEE of 2713 kcal/d and this changed at the end with an increase of 270 kcal/d so roughly 10% which is in line with the animal study.

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“Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233655/

Finally

So we see from the reduction in T3 that cell metabolism in general slows down while we see in skeletal muscle and brown adipose tissue that heat production goes up. Lean mass growth is slowed down.

What this essentially means is that the heat production increase is not just the additional energy expenditure that is observed, it also covers whatever the reduction is in metabolism. Keep in mind that 17~23% T3 reduction which by itself results in a lower heat production. The calorie-restricted mice had a 6% reduction in heat versus the control while the KD had an almost 8% increase in heat production versus control.

It all depends on the level of dietary protein and how it is combined with carbs or fat.

Longevity is associated by a low IGF-1 and T3 in those who live well above 90 years. As long as we can maintain or even build muscle strength, reducing protein and carb while increasing fat intake may be a good strategy to reduce overall tissue metabolism.

“Familial longevity is associated with decreased thyroid function” https://pubmed.ncbi.nlm.nih.gov/20739380/

The level of protein has a major role in signaling ideal reproduction times. Lowered levels indicate a less than optimal time with a need to be conservative.

On the menu you can choose:

  • with increased heat production (high fat)
  • without heat production (high carb)

The choice is yours.

———————————— T H E – E N D ————————————

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