A G protein-coupled receptor for fatty acids, GPR40 : a novel therapeutic target in treatment of adipotoxicity and glucose intolerance

2009 Fiscal Year Final Research Report

• Project/Area Number: 20790645
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: TOMITA Tsutomu Kyoto University, 医学研究科, 医員 (50402897)
• Project Period (FY): 2008 – 2009
• Keywords: GPR40 / G蛋白共役型受容体 / インスリン分泌 / 糖尿病 / 肥満 / 創薬

Research Abstract

To elucidate the regulation and pathophysiological implication of GPR40 in diabetes, we investigated GPR40 gene expression in pancreatic islets in Koletsky rats (fa^k/fa^k), a genetically obese model with a homozygous nonsense mutation in the ObR gene, as reported by us, and compared with lean littermates (+/+). In 14-week-old fa^k/fa^k with established glucose intolerance, GPR40 gene expression in pancreatic islets markedly (~1/3) decreased. Augmentation of insulin secretion in response to oleic acids was markedly attenuated in isolated islets from fa^k/fa^k. Tissue triglyceride levels were ~3-folds increased in pancreatic islets of fa^k/fa^k. Notably, mRNA expression of Pdx1, for which a putative binding domain is reported in the GPR40 promoter, was markedly (~1/2) decreased in pancreatic islets of fa^k/fa^k. Our results suggest a link between decreased GPR40 expression and dysregulated insulin secretion in pancreatic beta cells with lipid accumulation, where decreased Pdx1 gene expression may play a pivotal role in the regulation of GPR40 expression. The data also provide evidence for Koletsky rats as a suitable model for investigation of lipid accumulation and dysfunction in pancreatic beta cells.

Research Products

• [Journal Article] Relevant use of Klotho in FGF19 subfamily signaling system in vivo (2010)
  • Author(s): K. Tomiyama, R. Maeda, I. Urakawa, Y. Yamazaki, T. Tanaka, S. Ito, Y. Nabeshima, T. Tomita, S. Odori, K. Hosoda, K. Nakao, A. Imura, Y. Nabeshima
  • Journal Title: Proc Natl Acad Sci U S A 107(4) Pages: 1666-1671
  • Peer Reviewed
• [Presentation] Decreased gene expression of a G protein-coupled fatty acid receptor GPR40 in pancreatic islets of Koletsky rats (2010)
  • Author(s): T. Tomita, K. Hosoda, S. Odori, J. Fujikura, H. Iwakura, M. Noguchi, E. Mori, M. Naito, T. Kusakabe, K. Ebihara, H. Masuzaki, K. Nakao
  • Organizer: 14th International Congress of Endocrinology (ICE2010)
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2010-03-28
• [Presentation] G蛋白共役型受容体40(GPR40)の肥満・糖代謝異常における意義の検討 (2009)
  • Author(s): 冨田努, 細田公則, 小鳥真司, 藤倉純二, 岩倉浩, 野口倫生, 森栄作, 内藤雅喜, 海老原健, 益崎裕章, 中尾一和
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 群馬
  • Year and Date: 2009-04-23
• [Presentation] G蛋白共役型受容体40(GPR40)の肥満・糖代謝異常の発症・進展における意義の検討 (2008)
  • Author(s): 冨田努, 細田公則, 小鳥真司, 藤倉純二, 岩倉浩, 野口倫生, 森栄作, 海老原健, 平田雅一, 益崎裕章, 中尾一和
  • Organizer: 第29回日本肥満学会
  • Place of Presentation: 大分
  • Year and Date: 20081017-20081018
• [Presentation] g蛋白共役型-脂肪酸受容体GPR40の糖尿病でのインスリン分泌調整異常における病態生理的意義の検討 (2008)
  • Author(s): 冨田努, 細田公則, 小鳥真司, 藤倉純二, 岩倉浩, 野口倫生, 海老原健, 平田雅一, 益崎裕章, 中尾一和
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
  • Year and Date: 20080522-20080524
• [Presentation] 肥満を基盤とする耐糖能異常の発症・進展におけるg蛋白共役型脂肪酸受容体GPR40の意義の検討-遺伝性肥満Koletskyラットの膵島でのGPR40遺伝子発現- (2008)
  • Author(s): 冨田努, 細田公則, 小鳥真司, 藤倉純二, 岩倉浩, 野口倫生, 海老原健, 平田雅一, 益崎裕章, 中尾一和
  • Organizer: 第81回日本内分泌学会学術総会
  • Place of Presentation: 青森
  • Year and Date: 20080516-20080518