Molecular nutritional signaling via MCFA and ketone body receptors

• Project/Area Number: 18K19731
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
• Research Institution: Tokyo University of Agriculture and Technology
• Principal Investigator: Kimura Ikuo 東京農工大学, (連合)農学研究科(研究院), 教授 (80433689)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 中鎖脂肪酸 / ケトン体 / GPR84 / GPR109A / GPR41 / GPR43

Outline of Final Research Achievements

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 demonstrated 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.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、中鎖脂肪酸やその生体代謝物であるケトン体が、エネルギー源としてではなくシグナル伝達物質として、細胞膜上受容体を介して生理機能調節、特にエネルギー代謝制御に寄与する新たなメカニズムの一端を明らかにした。このようなケトン体とその受容体を介した分子栄養メカニズムの解明は、栄養管理による先制医療や予防医学、更にはケトン体受容体を標的とした代謝性疾患治療薬の開発に向けて、今後、本成果の応用が期待される。

Research Products

• [Journal Article] Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions (2019)
  • Author(s): Miyamoto J, Ohue-Kitano R, Mukouyama H, Nishida A, Watanabe K, Igarashi M, Irie J, Tsujimoto G, Satoh-Asahara N, Itoh H, Kimura I
  • Journal Title: Proc Natl Acad Sci USA Volume: 116 Issue: 47 Pages: 23813-23821
  • DOI: 10.1073/pnas.1912573116
  • Peer Reviewed / Open Access
• [Journal Article] Dietary mung bean protein reduces high-fat diet-induced weight gain by modulating host bile acid metabolism in a gut microbiota-dependent manner. (2018)
  • Author(s): Nakatani A, Li X, Miyamoto J, Igarashi J, Watanabe H, Sutou A, Watanabe K, Motoyama T, Tachibana N, Kohno M, Inoue H, Kimura I.
  • Journal Title: Biochem Biophys Res Commun. Volume: 501 Issue: 4 Pages: 955-961
  • DOI: 10.1016/j.bbrc.2018.05.090
  • Peer Reviewed / Open Access
• [Journal Article] Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway (2018)
  • Author(s): Lee Eun-Young、Zhang Xilin、Miyamoto Junki、Kimura Ikuo、Taknaka Tomoaki、Furusawa Kenichi、Jomori Takahito、Fujimoto Kosuke、Uematsu Satoshi、Miki Takashi
  • Journal Title: Journal of Endocrinology Volume: 239 Issue: 3 Pages: 267-276
  • DOI: 10.1530/joe-18-0241
  • Peer Reviewed / Open Access
• [Presentation] 食由来栄養素と脂肪酸受容体 (2019)
  • Author(s): 木村郁夫
  • Organizer: 第92回 日本内分泌学会学術総会
  • Invited
• [Presentation] 食由来脂肪酸と脂肪酸受容体を介したエネルギー代謝制御 (2018)
  • Author(s): 木村郁夫
  • Organizer: 脂質栄養学会第27回大会
  • Invited
• [Presentation] メタボリックシンドロームと腸内細菌 (2018)
  • Author(s): 木村郁夫
  • Organizer: 第33回日本乾癬学会
  • Invited
• [Presentation] 食由来腸内細菌代謝産物による宿主エネルギー代謝制御 (2018)
  • Author(s): 木村郁夫
  • Organizer: 第161回日本獣医学会学術集会
  • Invited
• [Book] 医学のあゆみ 特集号 (2019)
  • Author(s): 宮本潤基、木村郁夫
  • Total Pages: 312
  • Publisher: 医歯薬出版
• [Book] 腸内細菌叢 : 健康と疾患を制御するエコシステム（大野博司編） (2019)
  • Author(s): 木村郁夫
  • Total Pages: 203
  • Publisher: 羊土社
  • ISBN: 9784758103763
• [Remarks] 東京農工大学 木村研究室
  • URL: http://web.tuat.ac.jp/~kimura/