It’s been a while since someone has proposed a new theory of obesity. I’m still a believer in “a calorie is a calorie” but it’s always good to find out what may be driving us to overeat.

The latest addition is the Fructose Survival Hypothesis for Obesity. The diagram above was taken from an article published in the journal Obesity. The authors claim that their new theory explains and is consistent with the other theories that include the energy-balance hypothesis, the carbohydrate-insulin model, the protein-leverage hypothesis, and the seed-oil hypothesis. They’re depicted in the large red circles and also include genetics and the microbiome. It all seems complicated, to say the least.

Fructose Survival Theory Simplified

Let’s just focus on the fructose in the blue box and follow those arrows. The arrow that goes up simply suggests that people who eat more fructose-containing food and drinks increase their food intake and gain weight. Simple.

The arrow that angles down to mitochondrial stress leads to a whole host of metabolic changes, all of which result in the decrease or blockage of production of ATP and the increase in fat storage. The result is obesity, altered blood lipids, and a fatty liver.

This pathway is apparently related to getting ready for hibernation, but one gene with the ability to store fat to protect against starvation kicks in and we just gain weight. Of course, it’s more complicated with multiple enzymes involved, but in reality it just goes back to one thing: eating and drinking too much of, in this case, refined carbohydrates.

Questions about the Fructose Theory

We know how this potential theory of obesity involving fructose metabolism seems to work. There are at least three questions:

1. Does the source of fructose matter? In other words, is high-fructose corn syrup (HFCS) more likely to impact weight more than the fructose in grapes or watermelon? The research in animals and a human trial involved eating and drinking the calories in prepared mixtures, but what about real food?

2. They suggest a pathway where glucose can be made into fructose by being exposed to salt, umami, and dehydration. In the animal trial, I couldn’t find total body water ascertained nor what type of sodium might be more hazardous: table salt? MSG? Pink salt?

3. Would the theory apply to normal weight people eating just enough to maintain their weight as it is, regardless of diet composition? Or would people gain weight even while not overeating, regardless of diet? They tested for outcomes in animals and people who were overweight to begin with, but there’s no evidence that people couldn’t lose weight if they cut calories even while eating a high-fructose diet.

Chemical drivers of food behavior such as those proposed must be studied, if for no other reason than to see if there are negative effects for people who don’t follow the mainstream dietary recommendations and yet maintain a healthy body weight. All this research has led to the research group being awarded a patent on a pharmaceutical that would interfere with a specific enzyme called fructokinase. We’re interfering with what they claim to be a natural process against starvation. Is that safe?

The Bottom Line

The researchers and drug developers have spent over a decade researching the fructose theory of obesity and spent millions of research dollars. They have a patented pharmaceutical that may address the issue. But the one question that they must answer, besides discovering any harms in clinical trials, is this: would someone who ate a diet high in fructose and sodium be able maintain a normal body weight? Is a calorie a calorie? Until then, I’m not convinced.

What are you prepared to do today?

        Dr. Chet

References:
1. Obesity. 2023. https://doi.org/10.1002/oby.23920
2. Phil.Trans. R. Soc. B 378:20220230. https://doi.org/10.1098/rstb.2022.0230