The Vicious Cycle Causing Obesity

I need to slow down a bit and explain in detail the obesity model I condensed into the schematic image in the previous post. Even such a guru of linoleic acid toxicity as Tucker Goodrich apparently didn’t fully understand how it works. So, from the beginning — slowly. Here’s the diagram.

Where to start — from the end? This is a model of obesity development. The base image comes from a study on mouse obesity. At the end, there’s a large “WG,” meaning weight gain.

The entire lower half explains that the main activator of all three processes required for storing calories as fat is hydrogen peroxide (H₂O₂). It’s not uric acid — that was tested with negative results. The activator is specifically H₂O₂ produced by the enzyme xanthine oxidase (XO), which is part of the purine degradation pathway leading to uric acid.

This brings us to the vicious cycle shown in the upper half of the diagram. Here we have three inputs: a high-fat diet (HFD), meaning dietary fats; then glucose — specifically cytosolic glucose. More precisely, cytosolic glucose that was not phosphorylated quickly enough into G6P by the enzyme hexokinase (HK). It’s important here to understand the dynamics of glucose processing. And finally, we have linoleic acid, a substrate for aldehyde production under oxidative stress.

The rate of glucose entry into the cell is controlled by transporters across the cell membrane. Glucose outside the cell triggers nothing — it only matters once it crosses the membrane. If it enters slowly via GLUT1 transporters, phosphorylation is fast enough, and the level of cytosolic glucose doesn’t rise. But if insulin levels are high, the cytosol becomes flooded with glucose through GLUT4 transporters.

The polyol pathway begins with the enzyme aldose reductase (AR). It starts processing glucose only at high concentrations (Km ≈ 100 mM). The threshold isn’t sharp, but it’s written that above 10 mM it already converts glucose into sorbitol, which is then converted into fructose. At normal 5 mM levels, it does nothing. Really nothing? Here lies the core of the matter. AR is more than 1,000 times more efficient at processing toxic aldehydes (Km ≈ 0.02 mM) than glucose. Thus, AR is primarily a detoxification enzyme, and it’s a good thing when its activity increases during oxidative stress so that aldehydes such as 4-hydroxy-2-nonenal (HNE) are quickly degraded.

But what happens when we add more glucose — via insulin — to a cell already under oxidative stress and producing high levels of H₂O₂? The AR enzyme increases in quantity, and glucose is more easily converted into fructose. The presence of fructose triggers production of the enzyme ketohexokinase (KHK). The mere presence of KHK changes cell activity. Fructose thus acts as a powerful metabolic switch, shifting energy production from oxidative phosphorylation toward oxygen-free fermentation. It activates the AMPD2/XO/H₂O₂ pathway, suppresses deacetylases SIRT2 and SIRT1, reduces antioxidant protection, and initiates uric acid production. We usually blame high glucose levels, but here the real cause of elevated oxidative stress is the polyol pathway and fructose — not glucose itself. This can be confirmed by genetically disabling KHK production.

Fructose activates oxidative stress. If membranes contain enough omega-6 polyunsaturated fatty acids derived from linoleic acid, sufficient aldehydes will be produced to activate AR — and thus the polyol pathway. The vicious cycle closes and becomes increasingly self-reinforcing. It’s clear that once a certain threshold is crossed, the cell’s metabolism flips.

The main activators are:

• Omega-6 content in membranes
• Post-meal insulin and glucose levels
• Slow rate of glucose phosphorylation in the cytosol
• Rate at which the liver is flooded with glucose
• Rate of absorption in the digestive tract

How does dietary fructose enter this process? Can dietary fructose replace endogenously produced fructose from the polyol pathway? Probably yes, but dietary fructose behaves differently. When eating fruit, there isn’t much of it, and the digestive system converts most fructose into lactate or other metabolites. Moreover, fruit contains other active compounds that suppress fructose’s effects — such as resveratrol, quercetin, and other polyphenols. Their concentrations are low, but at higher levels they are known to be effective. Thus, dietary fructose differs significantly in its effects from endogenously produced fructose.

Every slowdown in food processing plays a role here — slow eating, firm food texture (carbohydrates), large starch granules, preferably linear rather than branched starch structure, slow gastric emptying, and so on. Therefore, any intervention that slows eating or digestion is covered by this model — including modern anti-obesity drugs that delay gastric emptying and slow intestinal activity.

Any disruption of this vicious cycle helps restore metabolism.

Specifically:

• Low fat content
• Low linoleic acid content in fats
• Slow carbohydrate digestion in the GI tract
• Compounds activating AMPK and inhibiting the AMPD2 pathway
• SIRT1 deacetylase activators such as acetate/vinegar, flavonols
• Antioxidants reducing H₂O₂ levels
• Low-carb or ketogenic diet

These methods should work — and have been proven effective in many studies — but only if oxidative damage is reversible. Some damage simply cannot be undone. If stem cell senescence occurs, recovery is very difficult. While oxidative stress may have removed dysfunctional cells through apoptosis, if stem cells are damaged, have entered senescence, and no longer divide, we cannot replace them. The changes may therefore be permanent.

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References are in the text.