Restricting Protein or Certain Amino Acids Helps Burn Fat
Recently, many social media influencers have been focusing on studies that surprisingly show how limiting protein in the diet leads to increased calorie burning, usually compensated by higher carbohydrate or fat intake. This is a very interesting area of research, with many unanswered questions.
The most frequently cited study was conducted on young, lean men. The results were highly surprising, hence the attention.
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| FGF21 is the primary factor behind the positive effects of restricting protein to around 9% of calories |
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| To maintain the same weight, caloric intake had to be significantly increased. This is related to energy expenditure through thermogenesis. LPHC: Low-protein, high-carb diet; LPHF: Low-protein, high-fat diet; HPD: Diet with standard protein content |
Is this practically applicable? Does it carry any risks? These questions still need to be answered. We don’t know. But we have other studies. For example, a recent study linked protein or branched-chain amino acid (BCAA) restriction to cellular senescence. As you already know, cellular senescence is a topic that greatly interests me. That’s why we’ll examine this study in more detail. It contains a lot of data, often very surprising.
The most remarkable aspect is the inconsistency in results. For example, there’s a significant difference between liver and adipose tissue senescence. The intervention only worked in males, with almost no effect in females. This raises many questions about the actual mechanism. Whenever such a complex dependency on a simple change in conditions occurs, we must look for hidden parameters that were left uncontrolled or unmeasured in the study. But we don’t yet know what those parameters are. Let’s take a closer look.
The primary aim of this research is to explore the impact of branched-chain amino acids (BCAA) on metabolism. These are three amino acids: leucine, isoleucine, and valine. It turns out that the effects of overall protein restriction — mainly the activation of the anti-senescence hormone FGF21 — are linked to these three amino acids.
They found that reducing BCAA levels in the diet protected male mice from the negative metabolic effects of both normal and high-protein diets. However, eliminating individual amino acids did not have this effect. They also observed that the response depended on sex—protein or BCAA restriction had minimal impact on female metabolism. I won’t repeat the study’s content here; you can read it yourself. I’m more interested in the connections.
What we know? Protein restriction increases FGF21 in both humans and mice. This enhances antioxidant protection in cells by boosting the PPP pathway, which produces NADPH for glutathione recycling. In adipose tissue, it promotes healthy tissue growth by increasing the number of small fat cells (hyperplasia), rather than enlarging existing ones (hypertrophy). It reduces cellular senescence in stem cells. According to this study, it works similarly in liver cells. Surprisingly, despite a significant increase in FGF21, the total number of senescent cells in the body rose with BCAA restriction. Adipocyte senescence increased. Unexpected. Even markedly higher FGF21 did not prevent adipocyte senescence.
If we look at it in more detail, it is probably related to the increased food intake on a protein or BCAA restricted diet. This higher food intake compensates for the increased heat production, increased energy expenditure. Otherwise, the weight of the mice would decrease. The same effect was observed in humans. They had to eat more calories to maintain the same weight. The increased heat production uses mechanisms dependent on the formation of hydrogen peroxide. This must release free fatty acids from the phospholipids of the mitochondrial membrane, usually linoleic acid from the second position using the enzyme iPLA2γ. The excess peroxide must be neutralized by glutathione peroxidase with enough NADPH molecules. But even FGF21 is apparently not enough. We have already encountered this, when burning fat, it is necessary to activate stronger sources of NADPH than the PPP pathway, the enzymes IDH2 and ME3 must be active. Acetate/vinegar, the shortest fatty acid can do this. How would the addition of acetate affect the results of the study? We do not know. And this raises another question: why didn't the study track the activity of gut bacteria? This data is completely missing.
Could insufficient production of acetate from the intestines be behind the different results between the sexes? Females have more body fat, more fat cells, and are better able to tolerate overeating. In males, short-term overeating damages fat tissue, and we see this in the activation of senescence. Couldn't the missing effect in females also be due to their greater resistance to overeating? The males hardly overeat. Why? Did something happen at the beginning of the study, so we don't see the overeating phase? Older females also almost matched their food intake to the control group. This could probably be easily detected by acetate supplementation, especially in males. Perhaps the effect of protein restriction would almost disappear, as it did in females.
This leads me to examine in detail the graphs of females first, where I assume there was no damage to the adipose tissue due to a lack of antioxidant protection. The study does not pay much attention to these graphs, because the changes are significantly smaller than in males. But for me they are a source of information about the effect of amino acids on an organism with undamaged fat cells. First, we will verify whether there has been senescence in the whole body.
Apart from the high protein diet (HP, HP-BR), there was no harm. Good news.
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| Males just for comparison |
We see that the glucose tolerance test (GTT) clearly shows the differences between the diets. The low protein (LP) group does not fare badly at all, nor does the BCAA-restricted group (CP-BR) fare badly either. Higher protein intake containing even more BCAAs clearly worsens the situation.
And what about gene expression?
In liver tests, we are interested in p16 as an indicator of cellular aging. Here, a low-protein diet clearly reigns supreme. The dependence is obviously not linear, because a very high protein content is better than a standard amount in the diet. In adipose tissue (iWAT), we are more interested in p21, here the best diet is a BCAA-restricted diet, a low-protein diet is not bad either, but statistical significance was not achieved. The effect is relatively small, I attribute this to the higher resistance of female adipose tissue from to be damaged. Restricting branched-chain amino acids (BCAAs) helps reduce cellular senescence and markers of inflammation, especially in middle and older age.
How does life expectancy relate to the amount of food consumed? Let's look at another study, the "longevity" study of mice.
According to the previous text, it might seem that protein restriction and BCAA only restriction provide similar results, but this is probably not the case. Females have a problem here. Is it related to the amount of food?
Note that while males consumed only slightly more food on the BCAA-restricted diet, females ate much more. Here I wonder, did the induction of cellular senescence in adipose tissue occur early in the experiment in males, thus increasing adipose tissue insulin resistance and decreasing voluntary food intake in males, while this occurred later in females? Do females therefore initially have a problem with the low BCAA diet? This could be the case.
If high food intake in a diet with limited amounts of protein or branched chain amino acids (BCAA) is associated with thermogenesis, this means higher production of hydrogen peroxide and higher requirements for antioxidant protection. If it is depleted and does not protect, damage occurs, there is a higher mortality. Paradoxically, the activation of cellular senescence has a protective effect, protecting DNA from damage by oxidative stress. We already know that, the cell would rather go into senescence and glucose fermentation than continue in oxidative phosphorylation with high production of ROS and increasing the risk of further DNA damage. This is the very principle of cellular senescence. In this way, cellular senescence of fat cells could even extend life at the cost of worsening some metabolic markers.
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