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Advances in Diabetes and Endocrinology

Fructose Metabolism: Implications for Obesity and Intestinal Cancer

Dr. Marcus Goncalves

Dr. Marcus Goncalves

The consumption of high fructose foods and beverages sweetened with high fructose corn syrup has increased significantly in the last four decades and more recently has been implicated in the prevalence of obesity and a rising incidence of cancer. Marcus D. Goncalves, MD, PhD, an endocrinologist with NewYork-Presbyterian/Weill Cornell Medical Center and physician-scientist with his own lab at Weill Cornell Medicine, pursues ongoing basic science and clinical investigations into the interactions between the endocrine system and how fructose drives obesity and affects cancer metabolism.

Fructose: The Road to Obesity and Back

Dr. Goncalves recently led a multicenter study, the results of which were published in the September 2021 issue of Nature, to examine dietary fructose metabolism. “We made a remarkable discovery that animals treated with a small amount of fructose had much longer intestinal villi, the small finger-like projections that increase the surface area of the intestine and are very important in nutrient absorption,” says Dr. Goncalves. “We developed new computational methods to measure the villi in many different mouse models, looking at over five different genetic backgrounds in male and female mice. We were the first to establish that this is a very consistent and reproducible finding: Fructose in the diet increases villus length, expanding the surface area of the gut and increasing nutrient absorption and adiposity in mice that are fed a high fat diet.”

The researchers gave the mice different challenges and nutrients, including lipid bolus and xylose. “Whether it was xylose, fructose, or lipid, we observed that the absorption was greater when the mice were given fructose,” notes Dr. Goncalves. “That has implications for many diseases, but most notably obesity because the Western diet is high in fructose. Many foods that predispose one to obesity contain fructose, including most ultra-processed foods. Estimates using the NHANES data suggest that 60 percent of the calories we consume are in ultra-processed foods and one in five calories of those foods is fructose. If what we found in mice is true in humans, it suggests that fructose is increasing the absorption of some of the other nutrients.”

Dr. Goncalves and his team explored this fructose finding further by comparing mice put on a low fat diet, a high fat diet with dextrose or glucose, and a high fat diet with fructose added. “As expected, the animals that were fed the high fat diet, whether it had fructose in it or not, gained more weight than the normal chow diet,” explains Dr. Goncalves. “What was surprising is that the animals fed the high fat and high fructose diet gained about 20 percent more weight than the high-fat diet, a statistically significant gain. Fructose having this previously unknown effect of improving absorption makes complete sense. The problem in humans is that fructose is available to us all day, every day so we are maximally absorbing all of our nutrients.”

Dr. Goncalves notes that studies have shown that obese individuals tend to have increased absorption. “We believe that is because they are eating more fructose. In future studies, we hope to be able to translate that data in humans.”

Dr. Goncalves and his research team further identified pyruvate kinase, an enzyme used to process glucose, as the molecular mechanism for the lengthened villus. “We determined that we could reverse the effect of fructose by giving a pyruvate kinase activator, which thwarts fructose from affecting the villi thereby preventing absorption,” says Dr. Goncalves. “We have studies ongoing testing this drug in mice with the idea that perhaps someday this could be a food additive that protects people from the effect of fructose and could have therapeutic implications for obesity.”

The Cancer Connection

In 2019, Dr. Goncalves and his colleagues in the Weill Cornell Medicine Meyer Cancer Center published the results of a multicenter study in Science showing that high fructose corn syrup consumption leads to larger tumors in the intestines of mice. “In that study, the adenomatous polyposis coli mice were predisposed to develop intestinal tumors,” says Dr. Goncalves. “We discovered that when animals were given moderate doses equivalent to 12 ounces of soda worth of fructose, the tumors substantially increased in size and tumor grade. Those mouse studies supported our hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.”

Today, Dr. Goncalves is exploring pyruvate kinase activator to combat colorectal cancer. “In another animal model, we gave the mice fructose and reproduced the effect that we initially saw – larger tumors,” says Dr. Goncalves. “We found that we can completely prevent that by giving the pyruvate kinase activator in tandem with fructose.”

The researchers are now moving to a clinical study of patients with colorectal cancer who are given a small dose of fructose before surgery. “First, we want to simply confirm that the fructose gets taken up by the tumors,” says Dr. Goncalves, co-principal investigator along with Alessio Pigazzi, MD, PhD, Chief of Colorectal Surgery at NewYork-Presbyterian/Weill Cornell. “The next study will involve using this drug to block fructose uptake and reverse the pyruvate kinase activity. We have a series of clinical studies planned that will hopefully identify this class of drugs as a treatment for colorectal cancer and in the future extend it to treat obesity.”

Dr. Goncalves does not believe metabolic therapies will ever be the primary treatment for cancer, but rather an adjunct to chemotherapy and radiation. “For example, for patients who have genetic diseases that develop intestinal tumors, such as the polyposis coli syndromes or adenomatous polyposis coli tumors, this drug may help them to get fewer or smaller tumors that can be treated throughout their lifetime,” he says.

Looking Ahead

As a clinician and translational scientist, Dr. Goncalves is eager to test more pyruvate kinase activators as anticancer therapeutic treatments. “Many of these drugs have been in clinical trials for other reasons and found to be extremely safe,” he says. “I would love to test some of these clinical compounds in our animal models and then ultimately test them in humans to get them to clinic as soon as possible.”

An advocate for public policy, Dr. Goncalves is also seeking to influence the United States Department of Agriculture’s dietary guidelines on sugar consumption. “Current guidelines allow up to 10 grams per day and I’m hoping that some of our data will help push the scientific committee to lower it to 6 grams the next time they review the guidelines. The more data that we can provide to help that cause, the better I believe it will be for our nation.”

Read More

Dietary fructose improves intestinal cell survival and nutrient absorption. Taylor SR, Ramsamooj S, Liang RJ, Katti A, Pozovskiy R, Vasan N, Hwang SK, Nahiyaan N, Francoeur NJ, Schatoff EM, Johnson JL, Shah MA, Dannenberg AJ, Sebra RP, Dow LE, Cantley LC, Rhee KY, Goncalves MD. Nature. 2021 Sep;597(7875):263-267.

High-fructose corn syrup enhances intestinal tumor growth in mice. Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, Pauli C, Morris R, Taylor S, Bosch K, Yang S, Wang Y, Van Riper J, Lekaye HC, Roper J, Kim Y, Chen Q, Gross SS, Rhee KY, Cantley LC, Yun J. Science. 2019 Mar 22;363(6433):1345-1349.

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