Metabolic benefits of dietary medium-chain fatty acids bypass hepatic ketogenesis

Saturated medium-chain fatty acids (MCFAs) are ketogenic nutrients, and their dietary intake has been linked to health benefits such as improved energy balance and increased insulin sensitivity. Here, we tested the hypothesis that MCFA-mediated hyperketonemia is required for these benefits. Using tissue-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout mouse models, we show that the hyperketonemia induced by oral administration of triacylglycerols with the MCFA octanoic acid (C8:0-MCT) is mediated by hepatic, but not intestinal, ketogenesis. Remarkably, acute reductions in food intake and body weight induced by C8:0-MCT in obese mice were independent of hepatic ketogenesis; likewise, chronic protection against weight gain and marked improvements in insulin sensitivity elicited by MCFA-rich diets did not require hepatic ketogenesis. These data demonstrate that dietary MCFAs are potent bioactive lipids capable of inducing metabolic benefits independently of their ketogenic properties.