Regulatory mechanism of hepatic glucose metabolism by ghrelin and LEAP2

• Project/Area Number: 20K08911
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Sakoda Hideyuki 宮崎大学, 医学部, 准教授 (50376464)
• Co-Investigator(Kenkyū-buntansha): 張 維東 宮崎大学, 医学部, 助教 (90753616) ; イスラム エムデイーヌルル 宮崎大学, 医学部, 研究員 (10870149) ; 中里 雅光 宮崎大学, フロンティア科学総合研究センター, 特別教授 (10180267)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ペプチド / 糖脂質代謝 / 臓器連関 / 肥満 / 生理活性ペプチド / グレリン / LEAP2 / 糖尿病

Outline of Research at the Start

生理活性ペプチドは、ホルモンとしての役割に加えて、自律神経や免疫を介した多臓器連関で生体の恒常性維持に働く。liver-expressed antimicrobial peptide 2 (LEAP2)は、肝臓や腸管から分泌される抗菌ペプチドで、グレリン受容体の内因性アンタゴニストである。申請者は、グレリンとLEAP2は、摂食と成長ホルモン分泌調節に関わる胃・肝臓臓器連関を示すことを報告した。本申請では、グレリンとLEAP2が肝臓で糖脂質代謝を調節する分子機序を解析し、ヒト糖尿病や肥満症、NAFLDでLEAP2を測定し病態との関連を明らかにしていく。

Outline of Final Research Achievements

To Analyze the molecular mechanism by which the endogenous antagonist of ghrelin, LEAP2, regulates glucose and lipid metabolism in the liver, we examined LEAP2 in pathological conditions.
Human LEAP-2 in CSF was significantly increased in the patients with bacterial meningitis. In bacterial meningitis, LEAP-2 is produced locally in the brain and may be useful as a potential biomarker. Administration of LEAP2 to calorie-restricted mice induced inflammation and more weight loss in both C57BL/6 J mice or Ghsr-KO mice. Our findings suggest that LEAP2 functions independently of GHSR, implying that LEAP2 affects physiology beyond the ghrelin-GHSR system.

Academic Significance and Societal Importance of the Research Achievements

グレリンのアゴニストが癌カヘキシアの治療薬として実用化されている。LEAP2がグレリンを阻害する機序や病態における役割を解析して、グレリンとLEAP2による摂食やエネルギー代謝調節機構を明らかにすることで、新たな治療薬やバイオマーカーの開発に貢献できる可能性が示された。

Research Products

• [Journal Article] Liver-Expressed Antimicrobial Peptide 2 is a Hepatokine that Predicts Weight Loss and Complete Remission of Type 2 Diabetes Mellitus After Vertical Sleeve Gastrectomy in Japanese Individuals. (2023)
  • Author(s): Nabekura H, Islam MN, Sakoda H, Yamaguchi T, Saiki A, Nabekura T, Oshiro T, Tanaka Y, Murayama S, Zhang W, Tatsuno I, Nakazato M.
  • Journal Title: Obesity Facts Volume: - Issue: 4 Pages: 392-400
  • DOI: 10.1159/000530733
  • Peer Reviewed / Open Access
• [Journal Article] Liver-expressed antimicrobial peptide 2 functions independently of growth hormone secretagogue receptor in calorie-restricted mice (2022)
  • Author(s): Islam Md Nurul、Zhang Weidong、Sakai Katsuya、Nakazato Yuki、Tanida Ryota、Sakoda Hideyuki、Takei Toshiki、Takao Toshifumi、Nakazato Masamitsu
  • Journal Title: Peptides Volume: 151 Pages: 170763-170763
  • DOI: 10.1016/j.peptides.2022.170763
  • Peer Reviewed / Open Access
• [Journal Article] Human liver‐expressed antimicrobial peptide 2 elevation in the cerebrospinal fluid in bacterial meningitis (2021)
  • Author(s): Sakai Katsuya、Shiomi Kazutaka、Mochizuki Hitoshi、Islam Md Nurul、Nabekura Hiroki、Tanida Ryota、Sakoda Hideyuki、Nakazato Masamitsu
  • Journal Title: Brain and Behavior Volume: 1 Issue: 5
  • DOI: 10.1002/brb3.2111
  • Peer Reviewed / Open Access