How fructose may contribute to obesity and cancer

Research is revealing how fructose can affect villi—the fingerlike projections that line the inside of the small intestine—to raise the risk of obesity and related cancers. SciePro / Shutterstock

Moderate amounts of the sugar fructose, like those found in fruits, are taken up and broken down by intestinal cells. But increased use of sweeteners containing fructose has led to a large rise in its consumption. The major sources of fructose in the American diet are now sugar-sweetened beverages and ultra-processed foods. Increased fructose consumption has been linked to a rise in obesity and related cancers such as colorectal cancer. But how fructose may contribute to these conditions is unclear.

A team of researchers led by Dr. Marcus Goncalves at Weill Cornell Medicine explored the effects of dietary fructose on cells in the gut. NIH’s National Cancer Institute (NCI), National Institute for Allergy and Infectious Diseases (NIAID), and National Institute of General Medical Sciences (NIGMS) supported the research. Results appeared in Nature on August 18, 2021.

Fingerlike projections called villi line the inside of the small intestine. The researchers found that mice fed high-fructose corn syrup for four weeks had villi that were 25-40% longer than those in control mice. Villi help absorb nutrients from food by increasing the surface area of the intestinal walls. The researchers hypothesized that longer villi would lead to increased nutrient absorption. This could lead to increased fat absorption and weight gain when combined with a high-fat diet.

To test this, the researchers fed mice a diet in which almost half of the calories came from fat. Some mice were given fructose in their diet, while the rest had none. The mice that ate fructose had longer villi and absorbed more fats from their diet than those not eating fructose. They also gained significantly more weight and fat mass. 

As a villus grows, new cells form at the base and migrate towards the tip. As the cells move towards the tip, away from blood vessels, they receive less oxygen. Cell death from oxygen deprivation, or hypoxia, at the villus tip limits the length of the villus. But the researchers found evidence that fructose lengthened the villi by improving the survival of cells at the tips.

To learn more, the researchers examined the effects of fructose on hypoxic human colorectal cancer cells. Upon entering cells, fructose is converted into fructose-1-phosphate (F1P). The researchers observed high levels of F1P in colorectal cancer cells in the presence of fructose. Fructose exposure also inhibited the last step of glycolysis, the glucose metabolism pathway. F1P interfered with one of the enzymes that catalyze this step, PKM2. When the researchers blocked the cells from making PKM2, fructose no longer affected cell survival. 

The researchers next engineered mice lacking either PKM2 or the enzyme that converts fructose to F1P. Fructose consumption did not lead to elongated villi in these mice, nor did it lead to increased fat absorption and accumulation. They also tried treating mice with a molecule, TEPP-46, that activates PKM2. TEPP-46 countered the effects of fructose, protecting against villus elongation, lipid absorption and fat accumulation.

Earlier, the team had found that fructose promoted tumor growth in mice that were genetically predisposed to colorectal cancer. In this study, they found that activating PKM2 with TEPP-46 prevented this effect.

These results suggest how the high levels of fructose found in Western-style diets could contribute to obesity and colorectal cancer. “Fructose is nearly ubiquitous in modern diets, whether it comes from high-fructose corn syrup, table sugar, or from natural foods like fruit,” Goncalves says. “Fructose itself is not harmful. It’s a problem of overconsumption. Our bodies were not designed to eat as much of it as we do.”

—by Brian Doctrow, Ph.D.