Do We Get Fat from BCAAs or SAAs? Or from ammonia?

In my previous post I showed results of studies on diets restricting certain specific amino acids. Overall, that “divine” construction kit consists of twenty amino acids, twenty building blocks. Some are straight sections, some are bent, some pieces allow flexibility, some allow branching—just like a classic children’s building toy. In the last post we talked about branched-chain amino acids (BCAAs). It seems that restricting them leads to weight loss in mice, but there are still some “bugs.” For example, it doesn’t work in female mice. Females are simply more resistant, and we basically don’t know what is happening in the body. I suggested the idea that since females inherently have a higher percentage of body fat, their fat tissue is more resistant to overload, e.g., when overeating. And BCAA restriction in mice is actually connected with increased food intake. So my conclusion is that the positive results in males are caused by activation of cellular senescence and insulin resistance specifically in fat cells, while in other parts of the body insulin resistance stays low thanks to increased levels of the hormone FGF21, so more energy gets burned as heat.

But we still have another 17 amino acids—could restriction of other amino acids also work? Yes, it does. There’s another study in mice that compared restriction of BCAAs with restriction of sulfur-containing amino acids (SAAs). There are only two: cysteine and methionine. Reducing these two in the diet of mice to one-sixth of their original levels led to very significant weight loss in both males and females. This is very interesting because the researchers compared the results directly with BCAA restriction and concluded that SAA restriction is much more effective. They even tested cycling the diet, adding back either methionine or cysteine, and found that cycling also works, and that both amino acids must be lowered at the same time, otherwise it doesn’t work. Then they tried to figure out the mechanism behind it. That’s where they hit a problem. It seems that reduced cysteine alone limits the formation of new fat (DNL) in cells, but they did not find the specific mechanism.

Comparison of results of diets restricting branched amino acids (BCAA) or sulfur-containing amino acids (SAA). AA – contains all amino acids, 1/3 – restriction of BCAAs or SAAs to one-third, 1/6 – restriction to one-sixth.

So let’s speculate a bit based on the results of this study. Looking at the graphs and tables, what struck me was that SAA restriction lowers taurine levels both in the fed and fasting state. This means the pathway converting cysteine to taurine is being suppressed, especially during fasting. It’s as if cysteine is instead being used more for glutathione synthesis. And we’ve long known that glutathione supports oxidative phosphorylation. Increased GSH is seen in fat tissue and in the liver—this is a good clue. During fasting, cystathionine metabolism probably shifts toward cysteine and glutathione production and away from taurine formation.

SAA restriction increases cyst(e)ine production from cystathionine during fasting but suppresses taurine synthesis. There is a significant increase in reduced glutathione (GSH) in the liver, which means stronger antioxidant protection.

SAA restriction activates acetate/acetyl-carnitine production, which probably activates SIRT1 and the acetylation/deacetylation of many enzymes for fat and glucose burning through oxidative phosphorylation.

The taurine pathway consumes oxygen—not much, but it could mean that under normal conditions, with excess cysteine, short-term oxygen deficiency may occur. Or conversely, during resting oxidative phosphorylation, where little oxygen is consumed but the most hydrogen peroxide is produced, taurine synthesis may be activated and consume oxygen. This increases cysteine production from cystathionine, which also releases ammonia. We have already touched on ammonia’s effects on cell metabolism. It’s one of the substances that can trigger pseudohypoxia, activate the transcription factor HIF1A, and switch cell metabolism from oxidative phosphorylation to glucose fermentation. The cell saves itself from damage. Potential pH changes and oxidative stress caused by ammonia are thus limited. Ammonia also reduces the activity of superoxide dismutase (SOD) and creates conditions for oxidative DNA damage. The state of cellular senescence then protects the cell from more serious harm.

Comparison of fat cell size distribution under restriction of branched (BCAA) and sulfur-containing (SAA) amino acids. The taller and wider the column is at the top, the more large cells are present, which is a sign of stem cell senescence and their insufficient differentiation into functional fat cells. It is clear that BCAA restriction produces many large cells and does not resolve fat stem cell senescence. SAA restriction to one-sixth fixes this.

SAA restriction increases AMPK activity (phosphorylation), which reduces lipogenesis (DNL). This is probably a result of higher acetate production as a product of increased fat metabolism due to GSH production support and higher levels of TCA cycle products.

Fat formation is a rescue mechanism if fuel burning with oxygen doesn’t work well, if too much superoxide and hydrogen peroxide are produced during burning. Such a state can also be caused by deamination associated with ammonia production. Ammonia reduces the main antioxidant pathway converting superoxide into hydrogen peroxide, the SOD enzyme. For the further conversion to water, sufficient reduced glutathione and enough NADPH molecules are necessary. It seems that restricting branched chain amino acids (BCAAs), but even more so restricting sulfur-containing amino acids (SAAs), can solve this problem. Deamination and ammonia formation are reduced, and in the case of SAAs, the pathway to GSH is additionally enhanced. That is probably the key difference between a BCAA-restricted diet and an SAA-restricted diet. BCAA restriction does not reduce oxidative stress and leads to fat stem cell senescence. 

But I don’t think the whole problem of increased fat formation arises on its own. Excess cysteine is probably only relative, and only at certain times. It will be linked with other problems, such as a lack of NADPH for antioxidant protection, or the need to use up excess oxygen during low energy demand for “something,” so cysteine gets used for taurine production instead of GSH. That can then lead to higher fat formation, because antioxidant protection won’t be sufficient when oxygen is suddenly needed for oxidative phosphorylation and for generating more energy.


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References:

Dietary sulfur amino acid restriction improves metabolic health by reducing fat mass


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