Role of fatty acid receptor GPR120 and GPR40 in oil-induce GIP secretion

• Project/Area Number: 16K09745
• 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: HARADA NORIO 京都大学, 医学研究科, 助教 (50530169)
• 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 / GIP / GLP-1 / 脂肪酸 / GPR40 / GPR120 / 肥満 / ＧＩＰ / 脂肪酸受容体 / K細胞

Outline of Final Research Achievements

Free fatty acid receptors GPR120 and GPR40 are expressed in enteroendocrine K cells, and their activation induces the secretion of the incretin GIP. However, the role of these receptors in fat-induced GIP secretion in vivo and the associated mechanisms are unclear. In this study, we investigated oil-induced GIP secretion in GPR120-knockout (KO) and GPR40-KO mice.
GPR120/GPR40 double KO mice showed no GIP secretion by oil. Oil-induced GIP secretion was reduced by 50% and 80% in GPR120-KO and GPR-KO mice, respectively, compared with wild-type mice. GPR120-KO and GPR-KO mice also exhibited substantially decreased levels of CCK that promotes bile and pancreatic lipase secretion. Notably, treatment with a CCK analog resulted in recovery of oil-induced GIP secretion in GPR120-KO mice but not in GPR40-KO mice. These results indicate that GPR120 and GPR40 are essential for oil-induced gastric inhibitory polypeptide secretion, and GPR120-induced GIP secretion is indirectly mediated by CCK.

Academic Significance and Societal Importance of the Research Achievements

肥満は様々な生活習慣病の中で治療が困難な問題であり、２型糖尿病や心血管疾患の危険因子となる。肥満の減少は糖尿病や動脈硬化疾患の発症や進展予防に寄与できる可能性がある。
GIPは腸内分泌Ｋ細胞から分泌されるインクレチンであり、膵臓β細胞からのインスリン分泌を増強する。またGIPは、高脂肪食餌誘発性肥満およびインスリン抵抗性を増強する。 したがって、脂肪誘発性GIP分泌のメカニズムを理解しその分泌を抑制することは、肥満症の治療戦略につながる可能性がある。

Research Products

• [Journal Article] Solid-phase extraction treatment is required for measurement of active glucagon-like peptide-1 by enzyme-linked immunosorbent assay kit affected by heterophilic antibodies. (2019)
  • Author(s): Hasegawa T, Komagata M, Hamasaki A, Harada N, Seino Y, Inagaki N
  • Journal Title: Journal of Clinical Investigation Volume: 10 Issue: 2 Pages: 302-308
  • DOI: 10.1111/jdi.12896
  • Peer Reviewed / Open Access
• [Journal Article] Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide signaling in adipose tissue. (2019)
  • Author(s): Yamane S, Harada N.
  • Journal Title: J Diabetes Investig. Volume: - Issue: 1 Pages: 3-5
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  • NAID: 120006634638
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• [Journal Article] Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion (2019)
  • Author(s): Liu Y, Harashima SI, Wang Y, Suzuki K, Tokumoto S, Usui R, Tatsuoka H, Tanaka D, Yabe D, Harada N, Hayashi Y, Inagaki N.
  • Journal Title: FASEB J. Volume: 33 Issue: 5 Pages: 6239-6253
  • DOI: 10.1096/fj.201801783rr
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• [Journal Article] Medium-chain triglyceride diet stimulates less GIP secretion and suppresses body weight and fat mass gain compared with long-chain triglyceride diet. (2019)
  • Author(s): Murata Y, Harada N, Yamane S, Iwasaki K, Ikeguchi E, Kanemaru Y, Harada T, Sankoda A, Shimazu-Kuwahara S, Joo E, Poudyal H, Inagaki N.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: -
  • Peer Reviewed
• [Journal Article] Free fatty acid receptor GPR120 and GPR40 are essential for oil-induced GIP secretion. (2019)
  • Author(s): Sankoda A, Harada N, Kato T, Iwasaki K, Yamane S, Ikeguchi E, Murata Y, Hirasawa A, Inagaki N.
  • Journal Title: J Diabetes Investig. Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Glucose-dependent insulinotropic polypeptide deficiency reduced fat accumulation and insulin resistance, but deteriorated bone loss in ovariectomized mice (2018)
  • Author(s): Shimazu-Kuwahara Satoko、Kanemaru Yoshinori、Harada Norio、Ikeguchi Eri、Ueda Yohei、Yamane Shunsuke、Murata Yuki、Yasoda Akihiro、Kieffer Timothy J、Inagaki Nobuya
  • Journal Title: Journal of Diabetes Investigation Volume: Epub Issue: 4 Pages: 0-0
  • DOI: 10.1111/jdi.12978
  • NAID: 120006708221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Issue: 2 Pages: 272-272
  • DOI: 10.1152/ajpgi.00054.2018
  • Peer Reviewed
• [Journal Article] The Effect of White Rice and White Bread as Staple Foods on Gut Microbiota and Host Metabolism (2018)
  • Author(s): Mano Fumika、Ikeda Kaori、Joo Erina、Fujita Yoshihito、Yamane Shunsuke、Harada Norio、Inagaki Nobuya
  • Journal Title: Nutrients Volume: 10 Issue: 9 Pages: 1323-1323
  • DOI: 10.3390/nu10091323
  • Peer Reviewed / Open Access
• [Journal Article] Glucose-dependent insulinotropic polypeptide is required for moderate high fat diet, but not high carbohydrate diet-induced weight gain. (2018)
  • Author(s): Maekawa R, Ogata H, Murase M, Harada N, Suzuki K, Joo E, Sankoda A, Iida A, Izumoto T, Tsunekawa S, Hamada Y, Oiso Y, Inagaki N, Arima H, Hayashi Y, Seino Y.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 6 Issue: 6 Pages: 111-112
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  • Peer Reviewed / Open Access
• [Journal Article] Whole-exome sequencing in a Japanese family with highly aggregated diabetes identifies a candidate susceptibility mutation in ADAMTSL3. (2018)
  • Author(s): Jambaljav B, Tanaka D, Nagashima K, Harashima SI, Harada N, Harada T, Fujiwara Y, Wang Y, Liu Y, Tabara Y, Matsuda F, Koizumi A, Inagaki N.
  • Journal Title: Diabetes Res Clin Pract Volume: 135 Pages: 143-149
  • Peer Reviewed
• [Journal Article] Effects of three major amino acids found in Japanese broth on glucose metabolism and gastric emptying. (2018)
  • Author(s): Mano F, Ikeda K, Joo E, Yamane S, Harada N, Inagaki N.
  • Journal Title: Nutrition. Volume: 46 Pages: 153-158
  • Peer Reviewed
• [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] 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] 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
• [Journal Article] The role of GIP receptor in beta-cell survival. (2017)
  • Author(s): Harada N and Inagaki N.
  • Journal Title: Diabetology International. Volume: In press Issue: 2 Pages: 137-138
  • DOI: 10.1007/s13340-017-0317-z
  • Peer Reviewed
• [Journal Article] Plasma incretin levels and dipeptidyl peptidase-4 activity in patients with obstructive sleep apnea. (2016)
  • Author(s): Matsumoto T, Harada N, Azuma M, Chihara Y, Murase K, Tachikawa R, Minami T, Hamada S, Tanizawa K, Inouchi M, Oga T, Mishima M, Chin K.
  • Journal Title: Ann Am Thorac Soc Volume: 13 Issue: 8 Pages: 1378-87
  • DOI: 10.1513/annalsats.201510-697oc
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sitagliptin monotherapy has better effect on insulinogenic index than glimepiride monotherapy in Japanese patients with type 2 diabetes mellitus: a 52-week, multicenter, parallel-group randomized controlled trial. (2016)
  • Author(s): Kondo Y, Harada N, Hamasaki A, Kaneko S, Yasuda K, Ogawa E, Harashima S, Yoneda H, Fujita Y, Kitano N, Nakamura Y, Matsuo F, Shinji M, Hinotsu S, Nakayama T, Inagaki N.
  • Journal Title: Diabetol Metab Syndr. Volume: 27 Pages: 13098-13098
  • NAID: 120005758426
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Ubc13 haploinsufficiency protects against age-related insulin resistance and high-fat diet-induced obesity. (2016)
  • Author(s): Joo E, Fukushima T, Harada N, Reed JC, Matsuzawa SI, Inagaki N.
  • Journal Title: Sci Rep. Volume: 31 Issue: 1 Pages: 35983-35983
  • DOI: 10.1038/srep35983
  • NAID: 120005867104
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nardilysin is required for maintaining pancreatic β-Cell Function. (2016)
  • Author(s): Nishi K, Sato Y, Ohno M, Hiraoka Y, Saijo S, Sakamoto J, Chen P-M, Morita Y, Matsuda S, Iwasaki K, Sugizaki K, Harada N, Mukumoto Y, Kiyonari H, Furuyama K, Kawaguchi Y, Uemoto S, Kita T, Inagaki N, Kimura T and Nishi E
  • Journal Title: Diabetes Volume: 65 Issue: 10 Pages: 3015-3027
  • DOI: 10.2337/db16-0178
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of clock genes in insulin secretion. (2016)
  • Author(s): Harada N and Inagaki N.
  • Journal Title: J Diabetes Invest. Volume: 7 Issue: 6 Pages: 822-822
  • DOI: 10.1111/jdi.12517
  • NAID: 120006491704
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of fat-induced gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide secretion from K cells. (2016)
  • Author(s): Yamane S, Harada N, Inagaki N.
  • Journal Title: J Diabetes Investig. Volume: 7 Issue: S1 Pages: 20-20
  • DOI: 10.1111/jdi.12467
  • NAID: 120005770746
  • Peer Reviewed / Open Access
• [Presentation] Obesity and type 2 diabetes in Japan (2018)
  • Author(s): Harada N.
  • Organizer: International Symposium on Advanced Patients Care
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms of gastric inhibitory polypeptide (GIP) secretion from K cells in response to nutrients. (2018)
  • Author(s): Harada N, Yamane S, Inagaki N.
  • Organizer: Asia Islet Biology and Incretin Symposium (AIBIS)
  • Int'l Joint Research / Invited
• [Presentation] インクレチンを介した臓器ネットワークについて. (2018)
  • Author(s): 原田 範雄 , 稲垣 暢也.
  • Organizer: 第22回日本病態栄養学会年次学術集会
  • Invited
• [Presentation] インクレチンGIP の栄養素に対する分泌機序について (2018)
  • Author(s): 原田 範雄，山根 俊介，稲垣 暢也.
  • Organizer: 第61回日本糖尿病学会年次学術集会
  • Invited
• [Presentation] Glucose-dependent insulinotropic polypeptide (GIP) deficiency improves obesity but worsens bone loss in ovariectomised mice. (2018)
  • Author(s): Kanemaru Y, Harada N, Kuwahara-Shimazu S, Ueda Y, Yamane S, Murata Y, Yasoda A, Kieffer TJ, Inagaki N.
  • Organizer: 53rd EASD Annual Meeting
  • Int'l Joint Research
• [Presentation] 長鎖脂肪酸受容体GPR120とGPR40は異なる機序で脂肪摂取時のGIP分泌に関与する. (2018)
  • Author(s): 三小田 亜希子, 原田 範雄, 岩﨑 可南子, 山根 俊介, 村田 由貴, 金丸 良徳, 鈴木 和代, 渋江 公尊, 原田 貴成, 城尾 恵里奈, 平澤 明, 稲垣 暢也.
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 転写因子Pancreatic duodenal homeobox-1(Pdx1)は加齢に伴うGIP分泌亢進に関与する. (2018)
  • Author(s): 池口 絵理, 原田 範雄, 金丸 良徳, 三小田 亜希子, 山根 俊介, 岩﨑 可南子, 今城 正道, 村田 由貴, 鈴木 和代, 城尾 恵里奈, 稲垣 暢也.
  • Organizer: 第31回日本糖尿病・肥満動物学会学術集会
• [Presentation] Role of gastric inhibitory polypeptide (GIP) in high fat diet-induced obesity and insulin resistance. (2017)
  • Author(s): Harada N, Yamane S, Inagaki N.
  • Organizer: Asia Islet Biology and Incretin Symposium (AIBIS)
  • Int'l Joint Research / Invited
• [Presentation] 過食肥満下におけるインクレチンGIPの生体内への影響について. (2017)
  • Author(s): 桑原 智子, 原田 範雄, 金丸 良徳, 山根 俊介, 村田 由貴, 三小田 亜希子, 岩崎 可南子, 城尾 恵里奈, 渋江 公尊, 原田 貴成, 池口 絵理, 藤原 雄太, 稲垣 暢也.
  • Organizer: 第60回日本糖尿病学会年次学術集会
• [Presentation] 卵巣摘出マウスにおけるGIP分泌欠損は体重増加を抑制するが骨量を減少させる. (2017)
  • Author(s): 金丸 良徳, 原田 範雄, 桑原 智子, 植田 洋平, 山根 俊介, 村田 由貴, 八十田 明宏, 稲垣 暢也.
  • Organizer: 第32回日本糖尿病合併症学会年次学術集会
• [Presentation] Effect of high fat diet ingestion on GIP secretion. (2016)
  • Author(s): 原田 範雄, 山根 俊介, 稲垣 暢也.
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-05-19
  • Invited
• [Book] 栄養素に対する腸管内分泌細胞からのインクレチン分泌, 糖尿病 (2018)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Total Pages: 2
  • Publisher: 日本糖尿病学会
• [Book] 消化管ホルモンと栄養代謝, Modern Physician (2018)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Total Pages: 4
  • Publisher: 新興医学出版社
• [Book] 脂肪摂取時のインクレチン分泌について, Islet equality. (2017)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Total Pages: 3
  • Publisher: メディカルビュー社
• [Book] BIO Clinica (2016)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Total Pages: 5
  • Publisher: 北隆館
• [Book] 日本臨床 74巻増刊1 新時代の臨床糖尿病学(上) (2016)
  • Author(s): 原田 範雄, 稲垣 暢也.
  • Total Pages: 7
  • Publisher: 日本臨牀社