Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions

Significance

Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are important alternative energy sources in a state of energy deficit or metabolic crisis. The consumption of ketogenic diets, such as low-carbohydrate and medium-chain triglyceride diets, and time-restricted feeding lead to ketogenesis, which influences longevity and health. β-Hydroxybutyrate also acts as a signaling molecule via GPR109A and GPR41; however, to date, the specific G protein-coupled receptors responsible for acetoacetate and its physiological functions remain unknown. In this study, we demonstrate that acetoacetate acts as an endogenous agonist of GPR43 by ligand screening in a heterologous expression system, and that it, rather than short-chain fatty acids, maintains energy homeostasis via GPR43-mediated lipid metabolism under ketogenic conditions.

Abstract

Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.