The sympathetic nervous system has been found to be activated by low doses of propionate, as well as production of fasting hormones was triggered, leading to insulin resistance and hyperinsulinemia in recent Harvard T.H. Chan School of Public Health research.
When chronically exposed to a dose of propionate equivalent to that used for preserving food animals gradually gain weight, and human studies have shown propionate to disrupt metabolic processes and lead to hyperinsulinemia; findings may have important public health implications due to the fact there are no particular limitation on use of propionate under its current 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.
415 million people are affected by diabetes around the globe, and incidence of diabetes is projected to increase over 50% by 2040. Genetic factors alone can’t account for the rapid increase of obesity and diabetes that has been occurring, dietary factors may include added chemicals we are exposed to that are used to preserve, process, and package food.
“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.
Propionate/propionic acid is a naturally occurring short chain fatty acid used commonly as a preservative to prevent mold growth in cheese, flavorings, baked goods, and in animal feed it is used as an energy source of sheep and dairy cows to increase glucose content of milk. Propionate has been shown to stimulate glucose production in animals in previous studies, and small scale human studies have demonstrated added the compound to bread was linked to high postprandial insulin levels which suggests a potential induction of postmeal insulin resistance.
Administering propionate directly to mice in this study was demonstrated to be associated with dose related increases in blood glucose and hyperglycemia, as well as elevated blood insulin levels; subsequently related increases in glucose production in the liver were found to be triggered by increased production of glucagon fasting hormones produced by pancreatic islets and FABP4 secreted by adipose tissue.
Propionate appeared to activate the sympathetic nervous system and trigger norepinephrine release which stimulated FABP4 and glucagon secretion rather than directly stimulate secretion of FABP4 or glucagon from isolated mouse islet or pancreatic tissues. Chemically blocking norepinephrine release or inhibiting stimulation of the sympathetic nervous system was confirmed in additional testing to prevent propionate induced hyperglycemia and inhibit propionate induced increase in FABP4 and glucagon plasma concentrations.
Animals exposed to chronic low dose of an amount of the compound equivalent to that which may be present in a human processed food diet was associated with the animals gaining significantly more weight than control animals; before weight gain became evident animals exhibited increased blood glucose, hyperglucagonemia, hyperinsulinemia, and elevated blood levels of FABP4. Genetically deleting FABP4 in mice chronically exposed to propionate stopped the animals from gaining weight and prevented insulin resistance.
“These results suggested that the effects of chronic propionate treatment are mediated, at least in part, by FABP4. 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.” according to the researchers.
To investigate effects in humans 14 healthy volunteers were recruited to conduct a randomized trial: one group consumed a meal containing the same amount of propionate that would be found in a processed food meal; while the other consumed the same meal without propionate. After a week the test was repeated but the foods to the groups were switched. Results showed those given the propionate had significant increases in glucagon, FABP4, and epinephrine shortly after eating, which “indicates propionate may act as a metabolic disruptor that can increase risk of obesity and diabetes in humans.”
“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.”
Using data from the 2 year DIRECT study to further investigate effects of weight loss interventions on circulating propionate levels and metabolism showed at baseline plasma propionate levels directly correlated with insulin resistance, as measured using the HOMA-IR index. Analyses showed after adjusting for weight loss following 6 months of dietary intervention the greater decline in propionate levels the better improvement in insulin resistance was.
“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.”
Based on their findings the researchers concluded: “Our findings may have implications for the current practice of food preservation. 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.”
Given the common use of propionate to processed foods the researchers suggest larger human trials with longer exposure times to different doses should be conducted to gain better understandings of the metabolic effects of propionate, and potential alternatives should be sought if appropriate.
