Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 47; pp. 23813 - 23821
• Main Authors: Miyamoto, Junki, Ohue-Kitano, Ryuji, Mukouyama, Hiromi, Nishida, Akari, Watanabe, Keita, Igarashi, Miki, Irie, Junichiro, Tsujimoto, Gozoh, Satoh-Asahara, Noriko, Itoh, Hiroshi, Kimura, Ikuo
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-11-2019
• Subjects: Alternative energy; Alternative energy sources; Animals; Biological Sciences; Body weight loss; Carbohydrates; Cecum; Diet; Diet, Ketogenic; Energy metabolism; Energy shortages; Energy sources; Fasting; Fatty acids; G protein-coupled receptors; HEK293 Cells; High fat diet; Humans; Intestinal microflora; Ketogenesis; Ketone Bodies - metabolism; Ketones; Ligands; Lipase; Lipid metabolism; Lipid Metabolism - physiology; Lipids; Lipoprotein lipase; Lipoprotein Lipase - blood; Low carbohydrate diet; Metabolism; Mice; Mice, Inbred C57BL; Microbiota; Nutrient deficiency; Nutrition; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - physiology; Signal Transduction; Starvation; Weight loss; Weight reduction; FFAR2; fasting; ketone body; low carbohydrate; gut microbiota
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1912573116

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.