The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans

The short-chain fatty acid propionateis a potent inhibitor of molds that is widely used as a food preservativeand endogenously produced by gut microbiota. Although generally recognizedas safeby the U.S. Food and Drug Administration, the metabolic effects of propionateconsumption in humans are unclear. Here, we report that propionatestimulates glycogenolysisand hyperglycemia in mice by increasing plasma concentrations of glucagonand fatty acid–binding protein4 (FABP4). Fabp4 -deficient mice and mice lacking liver glucagon receptorwere protected from the effects of propionate. Although propionatedid not directly promote glucagonor 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 studyin 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 propionatedose equivalent to that used for food preservationresulted in gradual weight gain. In humans, plasma propionatedecreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionatemay 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 propionateconsumption is warranted.