Hepatic Gluconeogenesis as a Means Against Weight Gain?
Provocative headline, right? Gluconeogenesis is the enzymatic production of glucose from other substrates, usually from lactate or glycerol. It occurs mostly in the liver, but it’s active in other organs too—I think even in the kidneys. That’s not important. It’s part of the so-called Cori cycle, where lactate produced by muscle exertion is recycled into glucose in the liver. Feel that? We know that exercise is healthy, including the production of lactate by muscle activity. We even have studies showing that adding lactate improves the metabolism of obese mice. When I wrote about this, I couldn’t imagine there could be another mechanism than the one where lactate facilitates the entry of acetate into cells via MCT1 membrane transporters. Maybe there is another mechanism paradoxically related to the activation of gluconeogenesis itself.
The headline could also have been something like:
Endogenous Production of Nonessential Amino Acids Treats Obesity.
But that wouldn’t sound as paradoxical, even though it basically says the same thing. If we change the diet of mice so that, instead of a broad spectrum of amino acids in proteins, the diet contains only essential amino acids (EAA), the other amino acids are synthesized from them in the liver. This replenishes the full assortment of amino acids needed to build new enzymes. In a mouse longevity study, the most successful diet was the one restricting nonessential amino acids (no NEAA) and providing plenty of essential ones (lots of EAA). This combination of amino acids turns on the synthesis of nonessential amino acids, which includes the pathway for aspartate synthesis. To do that, pyruvate carboxylase (PC) must be activated—the main regulator of gluconeogenesis. So it occurred to me that perhaps the activation of PC is the key player.
Let’s look at the TCA cycle tracing from the previous post. A lack of amino acids turned on the synthesis of aspartate from glycerol, that is, the production of a nonessential amino acid. An intermediate in this process is oxaloacetate (OAA), the direct product of PC. Thus, aspartate didn’t come through the whole TCA cycle via malate, but from the other side—from glycerol. When amino acids are abundant, another nonessential amino acid—glutamate—enters the TCA cycle very actively after being deaminated to α-ketoglutarate (αKG). We already know that in obese people more α-KG runs backward into citrate than in lean people. This slows the TCA cycle, but probably doesn’t activate PC sufficiently; with plenty of protein, there is simply a lot of aspartate. There’s no reason to activate PC and therefore activate gluconeogenesis. But somehow, in a mysterious way, activating gluconeogenesis seems to help. We saw this while examining sulfur amino acids. If enough H₂S is produced by the activity of CSE in processing cystathionine and cysteine, PC is activated via S-sulfhydration, and metabolism is corrected. So is it good to increase gluconeogenesis activity? After all, gluconeogenesis is the main enemy of diabetics! Why should gluconeogenesis help?
Maybe it’s not glucose that’s the problem. Maybe it’s increased sensitivity to glucose levels caused by aldehydes like HNE. Let’s recap the vicious cycle of obesity. To trigger it, it’s enough to shut off antioxidant protection; this initiates fat storage and the formation of HNE from peroxidation products of linoleic-acid-derived molecules stored in membrane phospholipids. That activates the enzyme aldose reductase (AR), which detoxifies HNE along with ALDH2. If ALDH2 activity is insufficient (for example due to HNE attaching to ALDH2), AR must activate more strongly—but AR also processes unphosphorylated glucose. This amplifies the metabolic impact of high glucose. Gluconeogenesis thus becomes enemy number one, because enhanced AR activity turns glucose into fructose, and fructose turns off antioxidant protection. The vicious cycle closes. Gluconeogenesis therefore becomes part of this cycle. A pathway that was once very useful becomes problematic in the presence of HNE.
Alright then—how is it possible that with a lack of NEAA, gluconeogenesis becomes beneficial again? Something must block the action of fructose. Does a lack of NEAA activate SIRT1, SIRT2, or AMPK? Yes, we already know this—it activates SIRT2! A lack of amino acids counteracts the effects of fructose. So there is a sufficient reason why specifically a lack of nonessential amino acids could break the vicious cycle of obesity.
We have a study on this: seven groups of mice with various amino-acid and fat content in their diets. Normal mouse chow, a diet with 10% fat (SFA), and a diet with 60% fat (HFD), each split into three groups: one with casein (SFA, HFD), one containing a casein equivalent in amino acids (CAA), and one without NEAA, containing only higher amounts of essential amino acids (EAA). In the image above you can compare the groups. Omitting nonessential amino acids and enriching with essential amino acids completely fixes the metabolism of mice on a high-fat diet—regardless of PUFA content, even when using the well-known obesity-inducing diet (D12492). Even after researchers first fattened the mice into obesity and then changed their diet by replacing nonessential amino acids with essential ones. How is that possible?
Notice something? Once again, a pathway considered terrible, harmful, raising blood glucose, has turned out—after closer examination—to be extremely useful. It is absolutely essential for maintaining sufficient antioxidant protection when resources are scarce; it generates glucose for use in NADPH production, for glutathione (GSH) recycling, and for ensuring the breakdown of hydrogen peroxide. And as many times before, a phenomenon generally considered negative is actually very useful. We’ve already seen this in the example of insulin resistance, the rate of fat storage, and now in the example of gluconeogenesis—the creation of new glucose. Only the presence of toxic compounds (HNE) alters these processes so significantly that they appear harmful. Remove the toxins, and these processes—mistakenly considered bad—will function normally again and protect you.
I'll add one more paragraph, because I kind of forgot that gluconeogenesis also activates the enzyme glucose-6-phosphatase (G6Pase). This enzyme regulates the level of G6P and thus the location of the HK1/HK2 enzymes on the mitochondrial membrane, the use of ATP molecules created by oxidative phosphorylation in the mitochondria to phosphorylate glucose, and in general, it is a very important regulatory enzyme. It therefore also affects the rate of glucose processing, the rate of glycogen formation and indirectly insulin resistance. Check out older posts.
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