Is ammonia from glutamine responsible for making us fat?

If we summarize the basic studies where mice on a high-fat diet remained thin or even lost already accumulated fat, we find that the following is effective:

Genetically switched off transcription factor HIF-1α, switching off (pseudo)hypoxia
High intake of flavonols suppressing HIF-1α, so turning off (pseudo)hypoxia
Genetic switching off of the NADPH oxidase NOX2, so deactivation of the source of superoxide and hydrogen peroxide during (pseudo)hypoxia
Labeling of the enzyme xanthine oxidase with ubiquinone and its removal, so removal of the largest source of superoxide and hydrogen peroxide during a fatty diet, i.e. prevention of entry into (pseudo)hypoxia
Knocking down UCP2 in pancreatic beta cells, i.e. lowering insulin levels and reducing H2O2 production, so preventing the triggering of (pseudo)hypoxia by reducing glucose entry into cells

So what is this about? Some process triggers extremely high levels of superoxide and then hydrogen peroxide, which triggers defensive changes in gene activation. What is special about it is the activation of the enzyme xanthine oxidase (XO), the output of which is urea. So it must be somehow related to amino acid metabolism. Well, I won't stress you out, I think it's the activation of glutamine and glutamate metabolism that I described in the analysis here. I found out that burning carbohydrates alone or fat alone does not require burning proteins (amino acids). But if we burn both at the same time, the TCA cycle must also add glutamine or glutamate to the burning process because of activity antiporters that transport important molecules through membranes.

During the oxidative deamination of glutamate in the mitochondria, ammonia is released. This happens precisely during the normal running of the TCA cycle, therefore it seems to me that if we increase the amount of processed glutamate by simultaneously burning carbohydrates and fats, ammonia poisoning will also increase and the cell must react to this. It activates the transcription factor HIF-1α and switches to transamination, the production of ammonia decreases, but at the same time part of the TCA cycle turns in the opposite direction and fats will be formed from amino acids. It does not happen on all cells at the same time, only on some. Most cells can therefore continue to work normally. The simultaneous burning of carbohydrates and fats (with activated DNL lipogenesis, see below) therefore increases the poisoning of mitochondria with ammonia. Switching the metabolism to glucose fermentation is a defense mechanism that reduces the symptoms of poisoning for surrounding cells.

Obese - pathway of glutamine metabolism towards fat storage during active lipogenesis (DNL), Lean - pathway of glutamine metabolism if fat is not stored.

But this does not apply if we manage to prevent carbohydrates from triggering the so-called de novo lipogenesis (DNL). If DNL is not triggered, everything will be fine even with simultaneous burning of carbohydrates and fats, amino acids will not need to be burned in the TCA cycle. This is very interesting and hopeful. Therefore, no poisonous ammonia will be produced and there will be no need to save the pH of the cell by activating (pseudo)hypoxia. We will also prevent the TCA cycle part from turning backwards and slowing down the metabolism. In addition, we will probably also prevent the activation of the XO enzyme and thus the formation of a large amount of superoxide and urea. How do we turn off DNL even when consuming carbohydrates? It is enough to activate the phosphorylation of the ACC1 enzyme using the AMPK enzyme. Phosphorylation of ACC1 stops the formation of new fats from amino acids and thus corrects the TCA cycle for oxidative phosphorylation.

Stopping the XO enzyme stops excess production of hydrogen peroxide and fat storage. Obesity is caused by stopping the degradation of the XO enzyme by the Cullin2 enzyme, it is caused by the peroxidation products of omega-6 linoleic acid, specifically 12/15(S)-HETE.

How exactly can we do this? By vinegar or acetate. Acetate works! I found another study that confirms that acetate might be the way to go. This time as glycerol triacetate (triacetin, E1518).

I have already written here about the fact that acetate can repair the metabolism by correcting obesity in mice and they lose weight to a normal weight. Now we have another study that confirms it. Importantly, we also know the mechanism by which it works from a previous study. And apparently it may possibly not only be acetate from the diet, it could also be acetate produced by liver peroxisomes during the metabolism of omega-3 fatty acids, e.g. alpha-linolenic acid (ALA).

Study on laboratory rats, 8 weeks of control diet and 8 weeks of experimental diet containing 30% energy as triacetin or MCT oil. Control diet - normal diet for rodents, Western diet - high-fat diet containing 46% energy from fat, Western diet + Triacetin - high-fat diet with replacement of part of the fat with Triacetin (glycerol with three acetate molecules attached), Western diet + MCT - high-fat diet with replacement parts of fats with medium chain oils.

Laboratory rats were first divided into two groups and fed a control diet or a high-fat diet for 8 weeks. Then the group on the high-fat diet was divided into three groups. One continued on the same high-fat diet, the second received triacetin instead of part of the fat, and the third received MCT oil instead of part of the fat. Overall, the percentage of calories from fat did not change. You can see the result in the picture, the use of triacetin within one week caused a huge change in metabolism such that the body weight decreased almost immediately to the level of the control group. Replacing fats with MCT oil also had an effect, but only as a preventive measure, MCT oil could not reverse the already disturbed fat metabolism. In particular, an increase in the caloric value of the food intake can be seen. Triacetin, on the other hand, caused an immediate reduction in caloric intake, reduced hunger. Perhaps the combination of MCT and triacetin would be interesting, because the percentage amount of triacetin in this study was very high, 65% of triacetin in fat. The fat content in the diet was 46% energy, so overall triacetin was 30% energy. For comparison, a study on mice with sodium acetate used 5% by weight in the diet, which could correspond to a total of about 10% energy, that is, 3x less acetate, and it worked very similarly.

The mechanism is already revealed to us by previous studies. By means of ACC1 phosphorylation, i.e. by means of the enzyme AMPK. But stopping the DNL process alone would not be enough. The effect of AMPK is much broader, the level of cytosolic acetyl-CoA is restored, it acetylates HIF-1α and turns off fermentation and stops pseudohypoxia, i.e. metabolism without the need for oxygen. HIF-1 activates NADPH oxidase (NOX2) and is a source of superoxide and hydrogen peroxide independent of insulin levels. Thus, acetate acts similarly to the genetic shutdown of HIF-1α. Another effect is the normalization of the direction of the TCA cycle, amino acids (proteins) will stop being used for fat formation, this will significantly reduce the amount of toxic ammonia released. Ammonia released during the processing of amino acids stops the activity of superoxide dismutase SOD and thus forces the transition to pseudohypoxia. Ammonia also activates the xanthine oxidase enzyme, which is another source of superoxide independent of insulin levels. Acetate therefore suppresses the generation of ammonia and the generation of superoxide and hydrogen peroxide by the enzyme XO. It stops the formation of ROS outside the mitochondria. All sources of superoxide and hydrogen peroxide that do not originate from the TCA cycle or the electron transport chain disrupt insulin signaling and proper control of metabolism by insulin.

So is ammonia responsible for our metabolic problems? I think in many cases yes.

A few more pictures of what ammonia does to the mitochondria of nerve cells. The substance MK-801 blocks the NMDA receptor, blocking this receptor eliminates the negative effects of ammonia.

Ammonium acetate reduces the activity of superoxide dismutase, thus increasing the level of superoxide, but decreasing the level of hydrogen peroxide.

Mn-SOD - superoxide dismutase, Catalase - catalase, GSH peroxidase - glutathione peroxidase (the main antioxidant), Glutathione reductase - the main restorer of reduced glutathione.

XO - xanthine oxidase, the main source of superoxide when mitochondria are exposed to ammonia. The main factor that turns on the metabolism of fat formation.

Blocking the NMDA receptor eliminates the effects of ammonia on mitochondria. MK-801 potentiates the effects of GLP-1 as a means of eliminating metabolic syndrome by turning off the NMDA receptor.

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References:

Disruption of Hypoxia-Inducible Factor 1 in Adipocytes Improves Insulin Sensitivity and Decreases Adiposity in HFD-fed Mice

Myricetin protects against diet-induced obesity

Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice

UCP2 KO mice exhibit ameliorated obesity and inflammation induced by high-fat diet feeding

Causes and Consequences of A Glutamine Induced Normoxic HIF1 Activity for the Tumor Metabolism

Metabolic Complementation between Glucose and Amino Acid Drives Hepatic De Novo Lipogenesis and Steatosis

Novel role of xanthine oxidase-dependent H2O2 production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain

Short Chain Fatty Acids Prevent High-fat-diet-induced Obesity in Mice by Regulating G Protein-coupled Receptors and Gut Microbiota

Dietary triacetin, but not medium chain triacylglycerides, blunts weight gain in diet-induced rat model of obesity