TY - JOUR
T1 - Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions
AU - Miyamoto, Junki
AU - Ohue-Kitano, Ryuji
AU - Mukouyama, Hiromi
AU - Nishida, Akari
AU - Watanabe, Keita
AU - Igarashi, Miki
AU - Irie, Junichiro
AU - Tsujimoto, Gozoh
AU - Satoh-Asahara, Noriko
AU - Itoh, Hiroshi
AU - Kimura, Ikuo
N1 - Funding Information:
JP16H01355, and JP18K19731, to I.K. and JP18K17920, to J.M.), the Japan Agency for Medical Research and Development (Grant JP17gm1010007, to I.K.), the Lotte Foundation (to I.K.), the Institute for Fermentation Osaka (to I.K.), the Food Science Institute Foundation (to I.K.), the Smoking Research Foundation (to I.K.), and the Uehara Memorial Foundation (to I.K.).
Funding Information:
We thank Mai Arita and Shizuka Kasuga for the in vitro assay, members of the Nisshin Oillio Collaboratory for valuable discussions, and Dr. Masafumi Fujimoto for advice on the kinetic-binding assay. This work was supported in part by research grants from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology (KAKENHI Grants JP15H05344, JP16H01355, and JP18K19731, to I.K. and JP18K17920, to J.M.), the Japan Agency for Medical Research and Development (Grant JP17gm1010007, to I.K.), the Lotte Foundation (to I.K.), the Institute for Fermentation Osaka (to I.K.), the Food Science Institute Foundation (to I.K.), the Smoking Research Foundation (to I.K.), and the Uehara Memorial Foundation (to I.K.).
Funding Information:
aDepartment of Applied Biological Science, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, Fuchu-shi, 183-8509 Tokyo, Japan; bJapan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Chiyoda-ku, 100-0004 Tokyo, Japan; cDepartment of Endocrinology, Metabolism, and Hypertension, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 612-8555 Kyoto, Japan; dDepartment of Endocrinology, Metabolism, and Nephrology, School of Medicine, Keio University, Shinjuku-ku, 160-8582 Tokyo, Japan; and eDepartment of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 606-8501 Kyoto, Japan
Funding Information:
ACKNOWLEDGMENTS. We thank Mai Arita and Shizuka Kasuga for the in vitro assay, members of the Nisshin Oillio Collaboratory for valuable discussions, and Dr. Masafumi Fujimoto for advice on the kinetic-binding assay. This work was supported in part by research grants from the Japan Society for the Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology (KAKENHI Grants JP15H05344,
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - FFAR2
KW - Fasting
KW - Gut microbiota
KW - Ketone body
KW - Low carbohydrate
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U2 - 10.1073/pnas.1912573116
DO - 10.1073/pnas.1912573116
M3 - Article
C2 - 31685604
AN - SCOPUS:85075239574
VL - 116
SP - 23813
EP - 23821
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 47
ER -