Dietary Propionate Has Exercise-Like Effects on Metabolism and Aerobic Exercise Capacity in Western-Diet Fed Mice

Introduction and Objective: Bacteria that produce the short-chain fatty acid (SCFA), propionate, are enriched in the gut of elite athletes, and flourish in response to regular exercise. SCFAs can have beneficial effects on skeletal muscle and other metabolic tissues; however, it is unknown whether propionate directly contributes to the beneficial metabolic effects of exercise. We tested whether dietary propionate can enhance metabolic health and aerobic exercise capacity (VO2peak) in Western-diet fed mice. Methods: Eight-week-old CD-1 mice were fed a Western diet (high-fat, high-sucrose) for 16-weeks with (WDP) or without (WD) 5% propionate (w/w). VO2peak, body composition, food intake, insulin sensitivity, and glucose tolerance were measured. Liver and skeletal muscle were collected for biochemical and histological analysis. Results: WDP had reduced body weight and decreased fat mass compared to WD, despite similar food intake. Random blood glucose and glucose tolerance were also significantly improved in WDP. Improved glucose homeostasis in WDP was associated with increased tissue glucose uptake and lower hepatic glucose production in response to insulin. WDP also displayed increased VO2peak, even in the absence of exercise training. In liver, WDP had reduced steatosis which was accompanied by significant decreases in the protein levels of several key lipid metabolism regulators, including perilipin-2 and lipid droplet-associated hydrolase. In muscle, propionate induced a shift toward a more oxidative fiber-type, consistent with enhanced glucose metabolism and aerobic capacity. Conclusion: Addition of propionate to a Western diet can improve whole-body metabolism and aerobic exercise capacity in mice. We identify propionate as a potential contributor to exercise-mediated improvements in metabolic health. Disclosure: A. Das: None. L.E. Smith: None. S. Acharya: None. M. Annambhotla: None. H. Pan: None. J. Dreyfuss: None. D.A. Rivas: None. S. Lessard: None. Funding: National Institutes of Health (DK129850 & DK124258)