Investigation of regulatory mechanisim of GIP secretion by fatty-acid binding protein 5 (FABP5)

• Project/Area Number: 16K09778
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kyoto University
• Principal Investigator: Yamane Shunsuke 京都大学, 医学研究科, 助教 (90582156)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: インクレチン分泌 / 脂肪酸結合タンパク / 細胞内局在 / Gタンパク質シグナル伝達調節因子 / 脂質代謝異常

Outline of Final Research Achievements

We examined FABP5 localization in K-cells before and after oral fat intakeusing electron microscopy and confocal microscopy.FABP5 was present both in the nucleus and in the cytoplasm of K-cells before loading. In contrast, 60 minutes after fat loading, the intranuclear localization has disappeared. The expression of Regulator of G protein signaling 4 (RGS4) was found to be elevated in the K cells of FABP5-deficient mouse. We clarified that both GPR120 and GPR40 are involved in GIP secretion after fat intake. Based on our results, it is suggested that GPR40 expressed in K-cells directly sense LCFA, and in contrast, GPR120 expressed in I-cells indirectly regulates GIP secretion in the presence of bile via CCK secretion.

Academic Significance and Societal Importance of the Research Achievements

肥満・2型糖尿病患者の数は増加の一途をたどっており、全世界的に重要な健康問題であるが、有効かつ安全性の高い治療法は未だ確立されていないのが現状である。本研究で注目しているGIPはその治療標的として大変有望であり、その制御に関わる重要な分子としてFABP5に着目し、作用機構の解明に着手している。本研究の結果、薬剤によるFABP5の阻害が脂肪誘導性GIP分泌や脂肪摂取時の体重増加を抑制することが明らかとなれば、FABP5を標的とした肥満症の新たな治療法の開発、創薬につながることが期待され研究の意義は大きい。

Research Products

• [Journal Article] Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice. (2018)
  • Author(s): Ikeguchi E, Harada N, Kanemaru Y, Sankoda A, Yamane S, Iwasaki K, Imajo M, Murata Y, Suzuki K, Joo E, Inagaki N.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 315
  • Peer Reviewed
• [Journal Article] Distribution and hormonal characterization of primary murine L cells throughout the gastrointestinal tract (2017)
  • Author(s): Suzuki Kazuyo、Iwasaki Kanako、Murata Yuki、Harada Norio、Yamane Shunsuke、Hamasaki Akihiro、Shibue Kimitaka、Joo Erina、Sankoda Akiko、Fujiwara Yuta、Hayashi Yoshitaka、Inagaki Nobuya
  • Journal Title: J Diabetes Investig Volume: 9 Issue: 1 Pages: 25-32
  • DOI: 10.1111/jdi.12681
  • NAID: 120006376021
  • Peer Reviewed / Open Access
• [Journal Article] Long chain free fatty acid receptor GPR120 mediates oil-induced GIP secretion through CCK in male mice. (2017)
  • Author(s): 19.Sankoda A, Harada N, Iwasaki K, Yamane S, Murata Y, Shibue K, Thewjitcharoen Y, Suzuki K, Harada T, Kanemaru Y, Shimazu-Kuwahara S, Hirasawa A, Inagaki N.
  • Journal Title: Endocrinology. Volume: In press Issue: 5 Pages: 0-0
  • DOI: 10.1210/en.2017-00090
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of Gastric Inhibitory Polypeptide Receptor Signaling in Adipose Tissue Reduces Insulin Resistance and Hepatic Steatosis in High-Fat Diet-Fed Mice. (2017)
  • Author(s): Joo E, Harada N, Yamane S, Fukushima T, Taura D, Iwasaki K, Sankoda A, Shibue K, Harada T, Suzuki K, Hamasaki A, Inagaki N.
  • Journal Title: Diabetes. Volume: 66 Issue: 4 Pages: 868-868
  • DOI: 10.2337/db16-0758
  • NAID: 40021434294
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Attenuated secretion of glucose-dependent insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance in ob/ob mice. (2017)
  • Author(s): Shimazu-Kuwahara S, Harada N, Yamane S, Joo E, Sankoda A, Kieffer TJ, Inagaki N.
  • Journal Title: Mol Metab. Volume: 19 Issue: 3 Pages: 288-288
  • DOI: 10.1016/j.molmet.2017.01.006
  • NAID: 120005997778
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 脂肪酸結合タンパク5 (FABP5) の腸管内分泌K細胞における局在に関する検討 (2017)
  • Author(s): 池口絵理 渋江公尊Yotsapon Thewjitcharoen 山根俊介 原田範雄 原田貴成 藤原雄太鈴木和代 大和田祐二 稲垣暢也
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] FABP5 is an essential modulator of fatty acid-induced GIP secretion in enteroendocrine K cells (2017)
  • Author(s): Shunsuke Yamane
  • Organizer: 3rd Korea-Japan Diabetes Forum
  • Int'l Joint Research / Invited
• [Presentation] Subcellular Translocation of Fatty Acid-Binding Protein 5 (FABP5) in Glucose-Dependent Insulinotropic Polypeptide (GIP)-Producing K-Cells: Re-Emerging Role of Transmission Electron Microscope (2017)
  • Author(s): Kimitaka Shibue, Yotsapon Thewjitcharoen, Shunsuke Yamane, Norio Harada, Takanari Harada, Yuta Fujiwara, Kazuyo Suzuki, Yu Wang, Keiko Furuta, Yuji Owada, Nobuya Inagaki
  • Organizer: ENDO2017
  • Int'l Joint Research