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.

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.

Propionate: Food Preservative Linked to Weight Gain and Metabolic Issues | Inverse

Scientists have identified another reason you should avoid ultra-processed foods like frozen pizza and boxed pastries. New research suggests that a common food preservative found in many has significant effects on metabolism that could contribute to obesity and diabetes. In a study on mice and humans published Wednesday in Science Translational Medicine, it led to elevated blood sugar — a symptom that can cause multiple long-term health problems if it goes unchecked for too long.

In the paper, researchers demonstrate that propionate, which is used widely in ultra-processed foods like bread, pizza, pastries, cereals, ultra-processed pasta noodles, flavored yogurts, and sausage to prevent the growth of mold, affects the metabolism of humans and mice in some worrisome ways. In mice, propionate in the diet led to higher levels of blood glucose, weight gain, and insulin resistance, all of which are warning signs of eventual diabetes and obesity. Then, in humans, they showed that relatively low doses of propionate were likewise associated with insulin resistance and elevated blood glucose. 

These results suggest that propionate, which is also produced naturally by the human microbiome, deserves a closer look.

This photo was shot on a Nikon D800 with a SB-900 at 1/2 on it, reflecting of the walls. The SB-900 as CLS Master triggerd another SB-900 at 1/4 shooting through a small 40x40 cm softbox positioned at an reflecting angle behind the Pizza.
Frozen pizza and other processed foods often contain propionate to prevent the growth of mold.

Gökhan Hotamişligil, Ph.D., a professor of genetics and metabolism at Harvard’s T.H. Chan School of Public Health and the corresponding author on the paper, tells Inverse that this research all started with the work of Hans Adolf Krebs — whose name you may remember from high school biology lessons about the Krebs cycle. One of Krebs’ lesser-known experiments, conducted on dogs in the 1900s, showed that propionate might not be as benign as it seems.

“He gave dogs propionate, then realized that it was increasing glucose production and increasing more than what he expected,” says Hotamişligil. Knowing about this experiment, and knowing how widely propionate is used as a food preservative, he wondered why this might have been happening.

Hotamişligil’s team replicated Krebs’ findings, showing mice that ate diets with concentrations of propionate similar to those in human food ended up gaining weight and showing unhealthy metabolic symptoms.

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Moving onto human subjects who only ate propionate-enriched foods for a short time, the team found similar metabolic abnormalities.

“In some ways, we weren’t surprised that this was increasing glucose production,” he says. What was surprising was just how profound the effects were. “Even a small amount was very powerful in increasing glucose production.”

The other surprise was the fact that propionate increases hormones that stimulate glucose production — the well-known hormone glucagon, as well as one the team discovered, called fatty acid–binding protein 4 (FABP4).

Cereals, too, often contain the chemical. It’s also produced by the human body, naturally.

Normally these hormones kick in when the body is very low on blood sugar, preventing a lethal drop in blood glucose levels. But strangely, propionate seems to signal to the brain that the body is in starvation mode, even when it isn’t. This causes the brain to send out glucagon and FABP4, which tell the liver to produce glucose for the body to survive on. This mistaken metabolic signal, over time, could lead to health problems, including diabetes and obesity.

Michelle Cardel, Ph.D, an obesity and nutrition scientist at the University of Florida who was not involved in the study, tells Inverse that these results are strong, especially since the team performed experiments on both mice and humans — rather than just mice.

“However, in terms of the human data, this was done in 14 lean, healthy, non-diabetic adults, so I think we need to be careful in extrapolating that to the general population, especially since they basically looked at the response right after just one meal,” she says. Longer-term studies will be needed to find out exactly what risk the food ingredient poses to human health, and Hotamişligil says he hopes that his work will encourage other researchers to pursue that research.

“At this point, I will refrain from making dramatic claims or recommendations,” he notes.

That being said, it probably won’t hurt to eat more whole foods and fewer servings of ultra-processed foods.

“I think there’s already enough data out there to demonstrate that we should be limiting our consumption of ultra-processed foods anyway, so to me, this doesn’t really change the recommendations,” says Cardel. “I think it adds to the literature as to why we should really be limiting our highly-processed food intake.” She points to a recently accepted National Institutes of Health study showing that humans who are given ultra-processed foods eat an average of 500 more calories per day than humans who are given access to whole foods like fresh meat and vegetables.

“Not only is it leading to excessive calorie intake, but also the augmented response in insulin, taken together, you can see how excess consumption of ultra-processed foods could be playing a significant role in the development of obesity and diabetes in the United States,” she notes.

Cardel recognizes that not everyone has access to organic whole foods like fresh vegetables, especially in lower-income neighborhoods where grocery shopping is done at convenience stores rather than well-stocked grocery stores. Even then, though, she says that healthier choices can be made within those limited situations. For instance, frozen vegetables are a totally reasonable alternative to fresh veggies. Even without those options, though, she says there’s still some room to make better choices.

“I would stick with traditional oats versus quick oats — when possible,” she says. “But if all you have available to you in your neighborhood is a bodega that sells these ultra-processed foods, I’d rather they eat the one-minute oatmeal than the bag of sugary cereal.”

Abstract: The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid–binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.