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In Which Organ Does the Vicious Cycle of Obesity Take Place?

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I got a question on X: “In which organ does the vicious cycle of obesity actually take place?” Well, I have to admit, those thoughts came so quickly that I haven’t really reflected on it much yet. The polyol pathway is active in the liver, but I’m not aware of its activity in adipose tissue. Fat synthesis takes place both in the liver and in adipose tissue. So for now, let’s stick with the hypothesis that it’s the liver. We actually have a nice study on a mouse model where they tested the knockout of fructokinase (KHK, the enzyme that activates fructose) both globally in the organism and separately in the digestive tract or in the liver. The results are very interesting. Turning off fructose processing in the digestive tract prevents fructose from entering the body fairly well; it also seems to suppress the craving for sweets and reduces the consumption of sweetened water. But it does not prevent metabolic syndrome or weight gain in any way. The result is fatty liver and obesity. Ther...
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The Vicious Cycle Causing Obesity

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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 c...
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Water, Salt, and the Polyol Pathway — AR as a Villain or Protector?

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In one earlier post, I briefly mentioned the work of Dr. Rick Johnson regarding the effects of fructose , where he also discussed the impact of high salt concentration and the problems caused by restricted water intake. Both create osmotic stress, which results in activation of the polyol pathway. Let’s explore the mechanism that might reveal some ways to improve the situation—or at least guide us on what to avoid. Let’s first see what happens when the enzyme KHK is knocked out , the enzyme responsible for phosphorylating (activating) fructose. In mice, we saw that eliminating KHK activation (KHK KO) strongly suppresses the effects of both endogenous fructose (produced in the liver from glucose) and dietary fructose . So what happens when water intake is restricted? Does it activate the polyol pathway? Can KHK knockout prevent that? Shutting down fructose metabolism (KHK-KO) has no effect on fructose levels in the hypothalamus during water restriction (WR). Is dietary fructose responsi...
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Amino Acids as Modulators of Insulin Resistance and the Rate of Glycogen Storage?

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New findings are emerging so quickly that I’m compelled to keep writing new posts. I simply have to share them, because they’re very interesting. So, let’s recap the latest understanding — my interpretation of the studies dealing with the regulation of glucose phosphorylation. Extracellular glucose enters the cell through GLUT1 transporters, and when insulin is present, also through GLUT4 transporters. It reaches the cytosol, where it awaits phosphorylation. If phosphorylation is too slow, cytosolic glucose levels rise and activate the enzyme aldose reductase (AR) and initiate the polyol pathway , i.e. sorbitol → fructose → KHK → H₂O₂ and fructose → AMPD2 → urate — a process moving toward insulin resistance as a protection against rapid flooding of the cytosol with glucose. It’s a mechanism to quickly reduce the rate of glucose entry into the cell because the subsequent processing rate has its limits. The next step of processing is phosphorylation by the enzymes HK1/HK2 . The rate depe...
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The Rate of Glucose Phosphorylation as a Cause of Insulin Resistance?

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Once again, insulin resistance. I have already discussed this phenomenon several times here — a phenomenon many scientists consider the cause of civilization diseases, especially obesity and type 2 diabetes. We have shown that insulin resistance (IR) is an overly general term that does not capture the various mechanisms of its formation — that IR has its own causes and is therefore a reaction to some condition, an evolutionarily developed defense mechanism, generally beneficial and thus cannot be the root cause . Since then, I have discussed several other potential root causes of IR on this blog. In the previous post , I was intrigued by the issue of glucose phosphorylation. Although it seems like a simple process, it hides many complexities. I’ll show you a paper in which the author examines this problem in detail . It demonstrates the relationship between glucose transporters GLUT4 and hexokinase HK2 and insulin. In the resting state, with low insulin levels, glucose transporters GLU...
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Does the Umami Taste Activate a Signal of Essential Amino Acid Deficiency?

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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, worki...
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A Fatty Diet Slows Down Metabolism Even Without Sugar Via Fructose!

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That sugar isn’t healthy is something almost everyone knows today, even if they don’t really care or restrict themselves. But that sugar could be harmful even without sugar in food? That sounds strange, doesn’t it? Do we have evidence, studies, results? Yes, I think we do. I found a nice PhD dissertation that tries to answer exactly this question. And the results are very interesting. I’ll try to summarize them briefly here. In discussions on X, I came across a great experimenter in the field of nutrition. He runs his blog at exfatloss.com . Recently, he raised an interesting point about the low-carb keto diet . For some people, it simply doesn’t work, and no one knows why. He observed this himself and shares his findings with others on his blog. The idea came to him while listening to lectures by Rick Johnson, M.D., on fructose research. Specifically, that the body produces fructose on its own, for example, with too much salty food and a lack of water, or when consuming food containin...
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