The combined results from a small-scale randomized human trial and studies in mice suggest that consuming propionate, a common food ingredient that is used widely to prevent mold, increases levels of hormones that are linked with diabetes and obesity. The research, headed by a team at the Harvard T.H. Chan School of Public Health, found that in mice, exposure to low doses of propionate activated the sympathetic nervous system, triggered the production of fasting hormones, leading to insulin resistance and hyperinsulinemia.

Tests showed that animals gradually put on weight when chronically exposed to a propionate dose equivalent to that used for preserving food, while a small study in human volunteers indicated that propionate may disrupt metabolic processes and lead to hyperinsulinemia. The investigators say their findings have important public health implications, given that there are no particular limitations on the use of propionate under its FDA-approved labeling.

“Understanding how ingredients in food affect the body’s metabolism at the molecular and cellular level could help us develop simple but effective measures to tackle the dual epidemics of obesity and diabetes,” said Gökhan S. Hotamisligil, the James Stevens Simmons professor of genetics and metabolism and director of the Sabri Ülker Center for Metabolic Research at Harvard Chan School. Hotamisligil is senior author of the team’s published paper in Science Translational Medicine, which is titled, “The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans.”

Diabetes affects about 415 million people worldwide, and the incidence is projected to increase by more than 50% by 2040, the authors wrote. Genetic factors can’t account for the rapid rise in both obesity and diabetes that’s occurred over the last half-century, suggesting that environmental and dietary factors must be involved. Dietary factors may include the chemicals that are used to preserve, process, and package our 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, PhD, associate professor of medicine at Tel-Aviv University’s Sackler School of Medicine, director of the division of endocrinology at Sheba Medical Center in Israel, and research fellow at Harvard Chan School.

One of these chemicals, propionate (propionic acid) is a naturally occurring short-chain fatty acid (SCFA) that is used widely as a food preservative to prevent mold growth in cheeses, baked goods, animal feeds, and flavorings. Prior studies have shown that the compound stimulates glucose production in animals, and so it is also used as an energy source for dairy cows and sheep, and to increase the glucose content of milk, the researchers noted. A previous small-scale study in humans has also demonstrated that adding propionate to bread was linked with high postprandial insulin levels, “suggesting a potential induction of postmeal insulin resistance.”

In their newly reported studies, the team demonstrated that administering propionate directly to mice was associated with dose-related increases in blood glucose and hyperglycemia, and elevated blood insulin levels. Propionate-related increases in glucose production in the liver were subsequently found to be triggered by increased productions of the fasting hormones glucagon, which is produced by pancreatic islets, and FABP4, which is secreted by adipose tissue.

However, propionate didn’t directly stimulate secretion of glucagon or FABP4 from isolated mouse pancreatic or islet tissues. Rather, propionate appeared to activate the sympathetic nervous system and trigger norepinephrine release, which then stimulated glucagon and FABP4 secretion. Tests confirmed that chemically blocking norepinephrine release or inhibiting sympathetic nervous system stimulation also prevented propionate-induced hyperglycemia, and inhibited propionate-induced increase in glucagon and FABP4 plasma concentrations.

Further studies in mice showed the chronic, low-dose exposure to an amount of propionate equivalent that which might be present in a processed food-based human diet, was associated with the animals putting on significantly more weight, as fat mass, than control animals. Even before the weight gain became evident animals given propionate in their drinking water exhibited increased blood glucose, hyperglucagonemia, elevated blood levels of FABP4, and hyperinsulinemia.

Interestingly, genetically deleting FABP4 in mice chronically exposed to propionate was enough to stop them from putting on weight, and prevented insulin resistance. “These results suggested that the effects of chronic propionate treatment are mediated, at least in part, by FABP4,” the authors wrote. “In this study, we report that exposure to the SCFA propionate, a food preservative, led to a rapid activation of the sympathetic nervous system and concomitantly an increase in the fasting hormones, glucagon, and FABP4, in the postprandial state in mice.”

To test the effects of propionate in humans the team designed a small-scale, randomized trial involving 14 healthy volunteers. One group ate a meal containing about the same amount of propionate that would be found in a processed food meal, and the other group ate the same meal, but without the propionate content. A week later the test was repeated, but the groups were switched. The results showed that individuals given the propionate-containing meal had significant increases in epinephrine, glucagon, and FABP4 soon after eating. The findings indicated that propionate may act as a “metabolic disruptor” that potentially increases the risk for diabetes and obesity in humans,” the researchers suggested.

“Similar to our observations in mice, the propionate-containing meal taken by human participants resulted in a significant increase in plasma norepinephrine, and a postprandial increase in both glucagon and FABP4, as compared to a placebo-supplemented meal … This rise in postprandial insulin counter-regulatory responses by propionate led to a significant decrease in postmeal insulin sensitivity … with a compensatory increase in serum insulin and C-peptide … These results support the conclusion that oral consumption of a very low dose of propionate was sufficient to liberate norepinephrine and release the fasting hormones glucagon and FABP4.”

The researchers also analyzed data from the dietary intervention randomized controlled trial (DIRECT), to investigate any effects of weight loss interventions on circulating propionate levels and metabolism. DIRECT was designed as a two-year study to study the effects on obese individuals or different weight loss diets, including a low-fat, restricted-calorie diet, a Mediterranean restricted-calorie diet, and a low-carbohydrate, nonrestricted-calorie diet.

An examination of data from the study showed that at baseline, plasma propionate levels directly correlated with insulin resistance, as measured using the homeostatic model assessment of insulin resistance (HOMA-IR) index. The analyses showed that, after adjusting for weight loss following six months of dietary intervention, the greater the decline in propionate levels from baseline, the better the improvement in insulin resistance. “Thus, in human obese participants, circulating propionate directly correlated with insulin resistance, and a greater reduction in propionate during dietary intervention was associated with a greater improvement in HOMA-IR index, regardless of dietary intervention or initial body weight.”

The authors say their findings are of particular concern given the widespread addition of propionate to processed foods, and the “compelling evidence that chronic hyperinsulinemia can drive obesity and metabolic abnormalities.” They suggest that studies in larger human cohorts with longer exposure times to different doses of propionate should be carried out to better understand the metabolic effects of the compound. And if appropriate, potential alternatives to propionate should be sought.

“Our findings may have implications for the current practice of food preservation,” they concluded. “Given that the FDA has declared propionate to be generally recognized as safe with no known adverse effects, there is currently no limitation on its utilization other than as required by good manufacturing practice … repeated daily exposure to propionate for prolonged periods, as evident in our chronic propionate treatment of mice, may have important implications for public health and should stimulate a renewed interest in examining the potential actions and underlying mechanisms associated with food components such as propionate in humans.”

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