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

Propionate activates the insulin counter-regulatory hormonal response in mice, resulting in insulin resistance and weight gain. A metabolic dysregulator in hiding Propionate is a short-chain fatty acid that is a commonly used food preservative. Tirosh et al. now show that propionate induces postprandial hyperglycemia in mice, resulting in a counter-regulatory hormonal response. Propionate increased norepinephrine release by the sympathetic nervous system, leading to an increase in circulating glucagon and the adipokine fatty acid–binding protein 4 (Fabp4), which jointly induced liver glycogenolysis and compensatory hyperinsulinemia. Long-term exposure of mice to a daily low dose of propionate resulted in a gradual weight gain and insulin resistance. Studies in humans highlight the potential contribution of propionate in the diet to the development of insulin resistance and obesity. 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.