Propionate is a naturally occurring short-chain fatty acid that can be beneficial to our internal health. It is also added to foods to help prevent the formation of mold, and is widely used as a preservative in baked goods, animal feeds and artificial flavorings. Harvard scientists recently warned that propionate could be a trigger that leads to insulin resistance. Consumption of propionate in foods appears to increase levels of several hormones that are associated with risk of obesity and diabetes.
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In an effort to better understand how propionate affects our health, researchers, led by Harvard T.H. Chan School of Public Health (in collaboration with researchers from Brigham and Women’s Hospital and Sheba Medical Center in Israel) conducted a study.
“’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. Hotamışlıgil, James Stevens Simmons Professor of Genetics and Metabolism and Director of the Sabri Ülker Center for Metabolic Research at Harvard Chan School.”1
The study, which was published online in Science Translational Medicine, combined data from a randomized placebo-controlled trial in humans and mouse studies. Results indicated that propionate can trigger a torrent of metabolic events that lead to insulin resistance and hyperinsulinemia, which is a condition marked by extreme levels of insulin. The study also found that chronic exposure to propionate in mice resulted in weight gain and insulin resistance.
“Harvard scientists call propionate a ‘metabolic disregulator in hiding,’ with the dose used to extend shelf life and preserve food sufficient enough to replicate a hormonal response.”1
The surging rates of diabetes, 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 preparation or preservation of food may be a contributing factor, but until recently there has been little research evaluating these molecules.
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Considering that more than 400 million people worldwide suffer from diabetes, and the rate of diabetes incidence is projected to increase 40% by 2040 despite efforts to curb the disease, there is real reason for concern.
“’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 in Israel, and research fellow at Harvard Chan School.”1
To begin their study, researchers first administered propionate to mice and found that it rapidly activated the sympathetic nervous system (which is responsible for the “fight or flight response”). This led to a surge in hormones, including glucagon, nor-epinephrine, and a newly discovered gluconeogenic hormone called fatty acid-binding protein 4 (FABP4). This caused the mice to produce more glucose from their liver cells, which led to hyperglycemia – a defining trait of diabetes. The researchers also found that when mice were treated with a chronic dose of propionate, equal to the amount typically consumed by humans, it led to significant weight gain and insulin resistance in the mice.
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Next, they wanted to determine how the findings in mice may translate to humans. To do this, the researchers established a double-blinded placebo-controlled study consisting of 14 healthy participants. The participants were randomized into two groups. Group one received a meal that contained one gram of propionate as an additive, and group two was given a meal that contained a placebo. They collected blood samples before the meal, within 15 minutes of eating the meal, and every 30 minutes after that for four hours.
The results of the study found that participants from group one (who consumed the meal containing propionate) had significant increases in nor-epinephrine as well as increases in glucagon and FABP4 soon after eating the meal. This result indicates that propionate may act as a “metabolic disruptor” that probably increases the risk for diabetes and obesity in humans.
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It is worth noting that the hyperglycemia (abnormally high levels of insulin) and hyperinsulinemia (extremely high levels of insulin) seen after exposure to externally administered propionate (during the study) contrast significantly to the beneficial metabolic effects attributed to internally produced propionate, along with other short-chain fatty acids (SCFAs) that are present in our bodies. In the colon, these short-chain fatty acid molecules are primarily produced by the fermentation of undigested carbohydrates, and offer several health benefits, such as post-meal fullness and a decrease in body weight and fat. However, this study found that higher amounts of propionate, carried along by its intestinal drug transporter, were found in overweight and obese study participants when compared to lean participants. They also found that the administration of propionate resulted in increased triglycerides and decreased high-density lipoprotein cholesterol.
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Unfortunately, humans are exposed to increasing amounts of propionate through the consumption of preserved processed foods and artificial flavorings. So, in order to determine the translational relevance of their study findings thus far, the researchers designed another study – a randomized, placebo-controlled, double-blinded crossover study to evaluate the metabolic effects of dietary propionate consumption in humans.
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The researchers recruited 14 lean and healthy participants and randomized them into two groups. The participants fasted for 8 hours and then some were given a mixed meal with 1g of calcium propionate, also known as E282, added (this 1g dose of propionate is equivalent to the most common amount humans consume when eating a processed food based meal), and others were given a mixed meal without propionate. A week later, the participants were provided with an identical mixed meal again, after crossover of the groups. Blood samples were collected right before the meal, within 15 minutes after the meal, and then were consistently collected every 30 minutes for the next 4 hours. They discovered that this nominal dose of propionate resulted in a significant increase in glucose in the blood after their meal.
Similar to their initial observations in mice, the propionate-containing meal consumed by the 14 lean and healthy participants resulted in a significant increase in plasma norepinephrine (think “fight or flight response”, as mentioned above with the mice) and a post meal increase in both glucagon (a hormone that works to raise the concentration of glucose and fatty acids in the bloodstream), and the newly discovered gluconeogenic hormone called fatty acid-binding protein 4 (FABP4); as compared to the placebo meal. The rise in hormones that work against the action of insulin (and raise blood glucose levels in response to low blood sugar) in the group that consumed the meal containing propionate led to a serious decrease in post meal insulin sensitivity.
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The researchers concluded:
“Human consumption of propionate at a dose used to extend shelf life and preserve food was sufficient to reproduce the hormonal response to acute propionate exposure observed in mice. Furthermore, chronic exposure of mice to an equivalent daily propionate dose resulted in an increase in plasma concentrations of the insulin counter-regulatory hormones, glucagon and FABP4, and the development of insulin resistance, hyperinsulinemia, and gradual weight gain. The relevance of propionate to insulin resistance and obesity in humans was also suggested in a large, long-term, dietary interventional study (DIRECT), in which the reduction in plasma propionate in response to a weight-loss diet was independently associated with improved insulin sensitivity.”1
Furthermore, the researchers wisely state in their study that there are alternatives that could be used for food preservation that would yield public health benefits, such as vinegar, essential oils and wheat starches. They also warn that repeated daily exposure to propionate used in food production and preparation for prolonged periods may have important implications for public health with regard to potential actions and underlying mechanisms associated with propionate that resides in the human body, stating:
“Given that the U.S. Food and Drug Administration 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. Here, we report that exogenous propionate leads to a rapid activation of the sympathetic nervous system, resulting in an increase in both glucagon and FABP4. The increase of both of these fasting hormones in the postprandial state drives enhanced endogenous glucose production, likely due to glycogenolysis, leading to hyperglycemia and compensatory hyperinsulinemia.”1
The U.S. Food and Drug Administration generally recognize propionate as safe. We certainly hope these new findings will warrant further investigation and research into propionate and potential alternatives that could be used in food preparation.
