Is fructose a poison or a helper? It worked 200 years ago, it doesn't work today.

I enjoy controversial topics, and fructose is unique in this regard. Some experts completely condemn it, but as I’ve mentioned before, we have consumed fructose in fruit throughout our existence. To my knowledge, it has never been an issue until the last century. What are we doing wrong?   

I’ll let you guess — what do you think? You see results from a study involving three low-fat diets (13% fat): mice on standard chow feed, starch-enriched feed, and sugar/sucrose-enriched feed (39%). For now, guess which curve corresponds to which diet. .

I will attempt here to formulate a way to avoid overeating based on presumed mechanisms. The way we eat, especially the rate of food intake, is crucial. We must not overload the biological systems available to us. Every overload causes lasting changes. 

First method: 

Higher protein intake improves satiety signaling because excess amino acids are converted to liver glycogen via gluconeogenesis, which precisely signals when to stop eating. 

Proteins are combined with fats; fats take a long time to stabilize optimal intake as per the body's needs. Combined with proteins, this is fine because the liver indicates when there is enough glycogen from gluconeogenesis, and fats are burned between meals. Glycogen consumption depends on fat utilization. Wherever fats or ketones can be used, they will be utilized. Fats will not be blocked by fructose from fruit or excess glucose because these won’t be consumed. De novo lipogenesis doesn’t occur, so responses to changes in fat intake might be quicker. This is the principle of a ketogenic diet.  

If we want to include carbohydrates in our diet, then we probably only have two other options:

Second method: 

To the previous protein and fat-based diet, you can add slow carbohydrates without fructose, i.e., starches or better add glucose/dextrose in beverages in small amounts. This leads to steady glycogen replenishment throughout the day without glucose spilling into the whole body. The carbohydrate intake rate must match glycogen production rate (about 10 g/hour in the case of metabolic syndrom?). Excess carbohydrates beyond this threshold are stored elsewhere, mostly in fat tissues, leading to overeating. This excess fat can only be burned between meals, which works smoothly only if there is no activation of KHK by fructose. Therefore, even slow carbohydrates shouldn’t contain sucrose/fructose. If you want sweetness, use glucose/dextrose. Proteins are best concentrated into one or two meals per day due to their much longer digestion time.  

Third method:

Surprisingly, this mixed diet of proteins, fats, and slow starches/glucose can be replaced for one-off occasions with a relatively large amount of fast carbohydrates, provided that these are consumed almost entirely fat-free and with large amounts of fruit/sugar/fructose. Why? Isn’t fructose bad? 

Starches had the worst results, while a high sugar content (39%) had the best. Why?

Here is the reason: activation of UCP1 and energy wastage via heat produced in brown adipose tissue. 

A single larger amount of fast starch or glucose is too much load on the liver and body overall, triggering the polyol pathway and causing the liver to produce fructose. In this case, higher fructose content is beneficial. It reduces the glucose/starch amount consumed at once and leads to the glycolytic conversion of glucose to lactate within the digestive tract and the body, not just the liver. Lactate is then slowly processed into liver glycogen, reducing fat storage and daily food intake. Glucose and insulin loads will be significantly lower compared to consuming starches alone. Fructose also ensures a perfect switch to carbohydrates as an energy source during and immediately after eating. Fats are suppressed both in combustion (due to missing CPT1) and in release from fat tissues (via suppressed PPP pathway and reduced antioxidant protection through low NADPH). H2O2 reduces lipolysis, reduces releasing of free fatty acids from fat tissue. This is highly desirable in this case since fuels should not be combined. Rapid carbohydrate burning occurs, converting to heat, reducing metabolic efficiency, and increasing energy wastage. That's what we want. We don't want to store energy. 

However, this comes with one critical condition: there must be no fats in this meal. Long-chain fats do not belong in very sweet carbohydrate-rich meals. Nor should they accompany large amounts of fruit, but coconut or MCT oil, or possibly vinegar, could be included. Medium and short-chain fats are immediately burned and further increase the tendency to waste energy from food as heat. This is the principle of Dr. Kempner's rice diet.  

Finally, what about polyunsaturated omega-6 fats?

The harmfulness of these fats depends on the environment in which they are present. Pure linoleic acid itself burns very well, faster than saturated fats, provided fat burning works properly, i.e., with sufficient antioxidant protection via reduced glutathione. Under these conditions, certain small amounts of polyunsaturated fats may not cause any significant harm. Problems arise if antioxidant protection is depleted, and if omega-6 is already stored as arachidonic acid in mitochondrial membranes instead of oleic acid. 

This is quite a complex issue because these polyunsaturated fats themselves demand higher antioxidant protection during their combustion and consume more NADPH.  Essentially, these fats can be burned on a ketogenic diet if there is no issue with NADPH molecule levels. When slow carbohydrates are added, the combination of fuels with glucose activates the PPP pathway for NADPH production, so no problem should arise. 

However, in combination with fructose and fast carbohydrates, it's different. Fructose suppresses NADPH production by inhibiting SIRT2 deacetylase. It increases ROS production to activate UCP through the release of signaling free fatty acids from membranes via PLA2. This requires higher H2O2 production. This mechanism works excellently without dietary fats or fats released from fat tissue. 

In an environment with fats primarily composed of monounsaturated oleic acid, this mechanism also works well without producing toxic oxylipins. However, in an environment with PUFA, it triggers lipid peroxidation, releasing toxic oxylipins from membranes, such as MDA or HNE, which can induce cellular senescence in fat tissue and lead to permanent insulin resistance. This is the fundamental basis of civilization-related diseases and the origin of metabolic syndrome and related diseases. In an environment rich in polyunsaturated fats, it is not advisable to increase oxidative stress with fructose and sugars. Such an environment requires the first two dietary methods, while the third is dangerous.  

What worked for centuries no longer works today! 

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References:

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice

SIRT2 deacetylates and activates glucose-6-phosphate dehydrogenase (G6PD) to protect cells against oxidative stress

Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow