The dietary factor

Consumption of propionate, an ingredient that’s widely used in baked goods, animal feeds, and artificial flavorings, appears to increase levels of several hormones that are associated with risk of obesity and diabetes, according to new research led by the Harvard T.H. Chan School of Public Health in collaboration with researchers from Brigham and Women’s Hospital and Sheba Medical Center in Israel.

The study, which combined data from a randomized placebo-controlled trial in humans and mouse studies, indicated that propionate can trigger a cascade of metabolic events that leads to insulin resistance and hyperinsulinemia — a condition marked by excessive levels of insulin. The findings also showed that in mice, chronic exposure to propionate resulted in weight gain and insulin resistance.

The study will be published online today in Science Translational Medicine.

“Understanding how ingredients in food affect the body’s metabolism at the molecular and cellular levels could help us develop simple but effective measures to tackle the dual epidemics of obesity and diabetes,” said Gökhan S. Hotamışlıgil, James Stevens Simmons Professor of Genetics and Metabolism and director of the Sabri Ülker Center for Nutrient, Genetic and Metabolic Research at Harvard Chan School.

More than 400 million people worldwide suffer from diabetes, and the rate of incidence is projected to increase 40 percent by 2040 despite extensive efforts to curb the disease. The surging number of diabetes cases, as well as obesity, in the last 50 years indicate that environmental and dietary factors must be influencing the growth of this epidemic. Researchers have suggested that dietary components including ingredients used for preparing or preserving food may be a contributing factor, but there is little research evaluating these molecules.

The findings indicate that propionate may act as a “metabolic disruptor” that potentially increases the risk for diabetes and obesity in humans.

For this study, the researchers focused on propionate, a naturally occurring short-chain fatty acid that helps prevent mold from forming on foods. They first administered it to mice and found that it rapidly activated the sympathetic nervous system, which led to a surge in hormones, including glucagon, norepinephrine, and a newly discovered gluconeogenic hormone called fatty acid-binding protein 4 (FABP4). This in turn led the mice to produce more glucose from their liver cells, leading to hyperglycemia — a defining trait of diabetes. Moreover, the researchers found that chronic treatment of mice with a dose of propionate equivalent to the amount typically consumed by humans led to significant weight gain in the mice, as well as insulin resistance.

To determine how the findings in mice may translate to humans, the researchers established a double-blinded, placebo-controlled study that included 14 healthy participants. The participants were randomized into two groups: One group received a meal that contained one gram of propionate as an additive and the other was given a meal that contained a placebo. Blood samples were collected before the meal, within 15 minutes of eating, and every 30 minutes thereafter for four hours.

The researchers found that people who consumed the meal containing propionate had significant increases in norepinephrine as well as increases in glucagon and FABP4 soon after eating. The findings indicate that propionate may act as a “metabolic disruptor” that potentially increases the risk for diabetes and obesity in humans. The researchers noted that while the U.S. Food and Drug Administration generally recognizes propionate as safe, these new findings warrant further investigation into propionate and potential alternatives that could be used in food preparation.

“The dramatic increase in the incidence of obesity and diabetes over the past 50 years suggests the involvement of contributing environmental and dietary factors. One such factor that warrants attention is the ingredients in common foods. We are exposed to hundreds of these chemicals on a daily basis, and most have not been tested in detail for their potential long-term metabolic effects,” said Amir Tirosh, associate professor of medicine at Tel Aviv University’s Sackler School of Medicine, director of the Division of Endocrinology at Sheba Medical Center, and research fellow at Harvard Chan School.

Other Harvard Chan School authors included Ediz Calay, Gurol Tuncman, Kathryn Claiborn, Karen Inouye, Kosei Eguchi, and Michael Alcala.

Funding for this study came from National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases grant K08 DK097145, as well as the Nutrition Obesity Research Center at Harvard grant P30-DK040561, the Cardiovascular, Diabetes and Metabolic Disorder Research Center of the Brigham Research Institute, and the Israeli Ministry of Health Research and Fellowship Fund.