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

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 containing umami flavor, i.e., glutamate. It seemed to him that this might explain his observations.

I have already discussed fructose here many times. I have also considered the relationship between fructose and polyunsaturated vegetable oils. My conclusion was, and still is, that peroxidation of these oils requires the activation of the enzyme ketohexokinase (KHK), also called fructokinase, because it is activated by the presence of fructose and serves to activate it. This suppresses antioxidant processes by reducing the recycling of GSH and NADPH. Specifically, among other things, it suppresses the deacetylases SIRT1 and SIRT2, which then leads to acetylation of G6PD and IDH2. This increases the amount of fatty acid peroxides, or rather prevents their breakdown. For KHK production to be triggered, only a very small amount of fructose produced in the liver from glucose via the polyol pathway is needed.

Without the KHK enzyme, diet has almost no effect on body weight in KO mice, even with higher food intake.

The study compares three diets in two groups of mice differing only in the presence (WT) or absence (KO) of genes for KHK enzyme production. The three diets differed in fat and sugar content: no sugar and low fat (LFD), no sugar and higher fat (HFD), and sugar with higher fat (HFSD).

Look for yourself—KO mice completely lack the KHK enzyme. It’s no surprise that a standard low-fat diet containing 70% carbs activates the polyol pathway. As we know, this helps lower blood glucose levels. Fructose helps store carbs as glycogen and fat. What’s not okay, however, is that the KHK enzyme is apparently activated even with a fatty diet without sugar. The diet composition table most likely shows weights of individual components, not calories. To get calorie ratios, some calculations are needed. Fat content in LFD / HFD / HFSD is 9.5% / 30.5% / 30.5%, carbs are 67% / 44% / 44%, fructose is 0% / 0% / 14%. We see that the “fatty” diet isn’t very fatty at all—it mainly contains milk fat and a bit of corn oil. Protein is the same, about 20%. All in all, quite an acceptable diet for humans—almost low-fat, I’d say.

Already in the first figure above, we see that the fatty diet, by activating KHK, triggered energy conservation and storage. No need to stuff yourself with sugar—starch and milk fat are enough. The rise in free fatty acids first promotes insulin secretion, so glucose storage remains rapid at first, and glucose levels are even lower. That’s how it should stay—but it doesn’t. Over time, insulin decreases, glucose storage slows, glucose levels rise, and the polyol pathway turns on to produce fructose. That’s enough.

Once the polyol pathway activates in week 10, the well-known story of metabolic problems unfolds. Fructose may still help lower glucose levels for a while (around week 16), but by then enzymes are acetylated, and metabolism has slowed. Fructose sets the enzyme activity ratios toward energy storage. But this applies only to the WT group.

Weight gain due to the presence of KHK. 

The KO group, with the KHK enzyme turned off, is in a completely different position. Increased insulin production probably occurs, followed by gradual decline, but higher glucose levels do not trigger KHK production, SIRT2 deacetylase is not suppressed, and antioxidant protection is preserved. This allows exactly the same energy expenditure as on a standard diet. Body weight remains stable even with higher food intake. Interestingly, in the KO group, dietary fructose even helps store glucose—less insulin is needed, and it likely activates glycolysis and lactate production already in the gut via bacteria.

Dietary fructose may actually be less problematic than fructose produced by liver enzymes. Surprising, isn’t it? And what about linoleic acid? Its amount in the diet didn’t change at all—only the internal environment changed, no longer promoting fatty acid peroxides. Linoleic acid only becomes problematic once oxidized into peroxides.

The KO group without KHK speeds up glucose metabolism under all diets.

Without KHK, energy expenditure as heat is the same across all diets, regardless of food composition.

And that’s not all. Removing KHK completely eliminated so-called crown-like structures in adipose tissue—dead fat cells damaged by peroxidized linoleic acid. Why does switching off KHK remove these structures entirely? Because the environment changed. This environment oxidizes linoleic acid into aldehydes that poison fat cells. By avoiding this oxidative environment and ensuring antioxidant enzyme activity, these structures don’t form.

The absence of KHK (KO) protects fat and liver cells from the effects of oxidized polyunsaturated fats—even in the presence of fructose (sugar in the diet).

And that’s still not all. The study also examined KHK’s effect on blood vessels—vasodilation and vasoconstriction, i.e., vascular smooth muscle response to stimulation. Again, shutting down KHK protected blood vessels to a large degree from the effects of both fatty food and sugar.

Putting it all together: the polyol pathway producing fructose in the liver is likely much more active today than in the past. One could assume this is due to modern, rapidly absorbed food that spikes glucose. But that’s probably not the only factor. There must be other modulators.

So I started searching and asking AI. It struck me as very similar to the effects of S-sulfhydration of enzymes such as SIRT1 to SIRT3, AMPK, PC, etc. Could S-sulfhydration also affect the polyol pathway? Turns out—it could. The first enzyme in this pathway is aldose reductase (AR). Look at the figure I found: hydrogen sulfide in nerve tissue completely eliminated AR.

Could this mean that the effects of sulfur amino acid restriction and taurine supplementation, which I discussed a few posts back, are actually due to shutting down the polyol pathway? Eliminating endogenous fructose production? The enzyme aldose reductase contains an active cysteine that could potentially undergo S-sulfhydration and functional modulation by hydrogen sulfide. If this modulation removes AR, as shown above, then even high glucose levels wouldn’t trigger sorbitol or fructose production, but instead activate the PPP pathway and produce lots of NADPH for glutathione recycling. Antioxidant protection ensured. The figure also clearly shows restoration of superoxide dismutase (SOD) and reduced levels of MDA, an aldehyde formed by polyunsaturated fatty acid peroxidation. And all this can apparently be achieved by enzymatically produced hydrogen sulfide.

So far, we don’t know how to avoid triggering the polyol pathway. From what works, it seems free fatty acid levels play a role—they rise during de novo lipogenesis (DNL). But even a low-carb or keto diet does not protect here. On the contrary, long-term carb restriction increases gluconeogenesis, which easily replaces carbohydrate intake. With high fat intake, the body burns mostly fats and ketones, and only a small glucose intake is enough to raise blood sugar since its disposal is low. Gluconeogenesis also depends on the amount of non-essential amino acids consumed, i.e., protein quality. Occasional protein restriction may help erase the history of overeating by S-sulfhydratation of polyol pathway enzymes.

Liver glucose production is also linked to stress, which releases free fatty acids and triggers the whole process of elevated glucose and higher likelihood of polyol pathway activation.

And of course, the polyol pathway is suppressed by acetate/vinegar, i.e., activation of SIRT1 and AMPK, but only under balanced or calorie-deficient intake. With excess calories, acetate does help safely store energy as fat, but not everyone would like that.

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References:

Role of ketohexokinase in fructose-induced insulin resistance and endothelial dysfunction

Hydrogen sulfide alleviates neural degeneration in streptozotocin-induced diabetic rats probably through reducing oxidative stress and aldose reductase expression

Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway