Metabolic regulation via ketone body receptors 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) GPR41 and GPR109A (1, 2); 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 (3). Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma ketone body levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, ketone body receptors-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, these 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. (1); Kimura et al., Proc Natl Acad Sci U S A. 2011 (2); Kimura et al., Physiol Rev. 2020 (3); Miyamoto et al., Proc Natl Acad Sci U S A. 2019