Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions

Junki Miyamoto, Ryuji Ohue-Kitano, Hiromi Mukouyama, Akari Nishida, Keita Watanabe, Miki Igarashi, Junichiro Irie, Gozoh Tsujimoto, Noriko Satoh-Asahara, Hiroshi Itoh, Ikuo Kimura

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)23813-23821
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number47
Publication statusPublished - 2019


  • FFAR2
  • Fasting
  • Gut microbiota
  • Ketone body
  • Low carbohydrate

ASJC Scopus subject areas

  • General


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