Does the Umami Taste Activate a Signal of Essential Amino Acid Deficiency?

Let’s continue searching for the source of obesity and metabolic disorders. In the series “Who will tell us we have eaten enough food”. I explored the mechanisms by which the body regulates food intake. What determines that the food we’ve eaten isn’t enough and we need to eat more? My conclusions are fairly simple. During the day, we collect food to have enough energy for sleep. Control is carried out through liver glycogen — during the day, we burn and store different forms of food in various tissues, and in the end, there has to be something left. This leftover of carbohydrates and amino acids is converted into liver glycogen. After a day’s consumption, there must be enough glycogen for rest and sleep. I think this is the basic energy regulation.

But sufficient energy is not enough for survival. A lack of essential amino acids leads to premature death in mice. That’s probably why there are auxiliary mechanisms — for example, one that ensures sufficient essential amino acids, working through the hormone FGF21. It influences the energy regulatory system so that more energy is consumed, converting excess nonessential amino acids into glucose and burning them as heat. Together with a higher preference for protein-rich food over sugar — that is, a preference for the umami taste — this increases food intake and essential amino acid consumption. That’s how it works in mice, but I believe it’s similar in humans.

However, if that still doesn’t ensure enough essential amino acids, another auxiliary mechanism likely kicks in to increase food intake — activation of the brain by excess glutamate, one of the nonessential amino acids. So, higher food intake is ultimately determined by nonessential amino acids (glutamate), whose excess indicates a shortage of essential amino acids necessary for the meaningful use of nonessential ones. This means they were neither incorporated into enzymes or other proteins nor used for ATP or heat production. As an emergency solution, the body opts to eat more food — even at the cost of storing the surplus as fat. A too-low intake of essential amino acids is a life-threatening condition, and stored energy may come in handy.

AR – aldose reductase

Let’s return to fructose and the polyol pathway. If we trace the activation of this pathway, the first enzyme at its entry point is aldose reductase (AR). Influencing this enzyme through “decoration” will thus have a fundamental impact on metabolism. I have already speculated here that hydrogen sulfide likely interacts with AR. But the primary trigger for AR is a high glucose level. Then important cofactors are needed — NADPH and G6P.

What caught my attention is that the AR enzyme processes unmodified glucose. That’s strange because glucose entering the cell is immediately phosphorylated by hexokinase or glucokinase using ATP to glucose-6-phosphate (G6P). That would mean that AR is activated only when there is either a large excess of glucose at that moment or a significant shortage of ATP molecules. If all glucose is phosphorylated into G6P, AR has nothing to process — therefore, it produces neither sorbitol nor fructose. Does activation of KHK by fructose — and thus fat storage — relate to a lack of ATP in the cytosol? Does insulin resistance prevent activation of the polyol pathway? Low insulin levels are considered a protective factor — it makes sense: glucose outside the cell doesn’t hurt, but inside the cell it must be phosphorylated immediately.

It seems that the polyol pathway and fructose regulation system for shifting from oxidative phosphorylation to anaerobic glucose fermentation is much more general and present in many tissues. Perhaps it’s a basic system indicating that more glucose has entered the cell than can be processed quickly.

Low cytosolic glucose levels do not open the polyol pathway and do not activate urea formation.

High cytosolic glucose levels activate fructose formation via the polyol pathway and the removal of AMP through AMPD2 and IMP in the form of urea.

Activation of the polyol pathway due to ATP deficiency — that is, by unphosphorylated glucose — can lead to activation of uric acid production, which subsequently moves the enzyme NOX4 into mitochondria. There, its activity halts the TCA cycle and oxidative phosphorylation. A similar effect comes from glutamine/glutamate deamination — the resulting ammonia must also be removed through the urea cycle. Acetyl-CoA formed from beta-oxidation of fats then won’t be used for recycling NADH and oxidative phosphorylation but for citrate production for subsequent fat synthesis. So it’s a sort of battle between the activation of glucose phosphorylation and ATP production, or activation of the polyol–fructose–urea pathway and fat production.

We know that fructose molecules themselves can cause ATP depletion, but fructose without glucose does not activate the polyol pathway. For that, unphosphorylated glucose in the cell is required. This perfectly fits the risk of an excessively fast rate of carbohydrate intake and absorption in the digestive system, a rapid rise in blood glucose levels, and a higher risk of fat formation in the liver. No additional chemical stimulators are needed — the polyol pathway alone is enough.

Is it possible that acetate helps ATP production and thus prevents activation of the polyol pathway? There are likely several mechanisms at play, complementing each other.

Now let’s return to uric acid. The raw materials for urea production include molecules like AMP/IMP formed during purine metabolism. Let’s look at a study showing how monosodium glutamate in food activates overeating through the enzyme AMPD2 by influencing the brain, urea formation in the liver, etc.

Glutamate itself affects overeating more than fructose. This is because fructose mainly acts as a switch, while glutamate is an excellent substrate for gluconeogenesis, during which nitrogen is removed as ammonia — see an earlier post. It thus activates the shift of cells from oxidative phosphorylation to fermentation. Whether the initial trigger is a change in pH or urea doesn’t matter much — the result is always problematic pseudohypoxic metabolism.

Monosodium glutamate is much worse than fructose.

Monosodium glutamate stimulates urea production. Inhibition of the AMPD2 enzyme prevents xanthine oxidase activity and all its negative consequences.

The activity of enzymes breaking down purines is very taxing for cells. Interrupting this pathway anywhere almost completely suppresses its negative metabolic effects. See the earlier post about xanthine oxidase or the enzyme AMPD2. This mechanism even affects behavior in mice through activation of AMPD2 in nerve cells of the hypothalamus. The brain makes them eat more. Could it be that glutamate convinces the brain you’re short on essential amino acids and is trying to save you? I think that’s quite possible.

A lack of essential amino acids leads over time either to overeating or to a shortened lifespan. Take your pick. I’d choose the third option — to eat proteins containing as many essential amino acids as possible, so the body doesn’t have to deal with their shortage by overeating. And watch out for flavor enhancers!

It’s complicated, but over time, we’ll solve all the mysteries — I believe that.

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References:

Aldose reductase, fructose and fat production in the liver

Umami-induced obesity and metabolic syndrome is mediated by nucleotide degradation and uric acid generation