2. Academic Validation
  3. LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor

LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor

  • Cell Metab. 2018 Feb 6;27(2):461-469.e6. doi: 10.1016/j.cmet.2017.10.016.
Xuecai Ge 1,  Hong Yang 2,  Maria A Bednarek 3,  Hadas Galon-Tilleman 2,  Peirong Chen 2,  Michael Chen 2,  Joshua S Lichtman 2,  Yan Wang 2,  Olivier Dalmas 2,  Yiyuan Yin 2,  Hui Tian 2,  Lutz Jermutus 4,  Joseph Grimsby 5,  Cristina M Rondinone 5,  Anish Konkar 5,  Daniel D Kaplan 6
Affiliations

Affiliations

  • 1 NGM Biopharmaceuticals, South San Francisco, CA 94080, USA. Electronic address: xge2@ucmerced.edu.
  • 2 NGM Biopharmaceuticals, South San Francisco, CA 94080, USA.
  • 3 Department of Antibody Discovery & Protein Engineering, MedImmune Ltd, Cambridge CB21 6GH, UK.
  • 4 Department of Antibody Discovery & Protein Engineering, MedImmune Ltd, Cambridge CB21 6GH, UK; Department of Cardiovascular and Metabolic Disease Research, MedImmune LLC, Gaithersburg, MD 20878, USA.
  • 5 Department of Cardiovascular and Metabolic Disease Research, MedImmune LLC, Gaithersburg, MD 20878, USA.
  • 6 NGM Biopharmaceuticals, South San Francisco, CA 94080, USA. Electronic address: dkaplan@ngmbio.com.
PMID: 29233536 DOI: 10.1016/j.cmet.2017.10.016
Abstract

Ghrelin, an appetite-stimulatory hormone secreted by the stomach, was discovered as a ligand for the growth hormone secretagogue receptor (GHSR). Through GHSR, ghrelin stimulates growth hormone (GH) secretion, a function that evolved to protect against starvation-induced hypoglycemia. Though the biology mediated by ghrelin has been described in great detail, regulation of ghrelin action is poorly understood. Here, we report the discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist of GHSR. LEAP2 is produced in the liver and small intestine, and its secretion is suppressed by fasting. LEAP2 fully inhibits GHSR activation by ghrelin and blocks the major effects of ghrelin in vivo, including food intake, GH release, and maintenance of viable glucose levels during chronic caloric restriction. In contrast, neutralizing antibodies that block endogenous LEAP2 function enhance ghrelin action in vivo. Our findings reveal a mechanism for fine-tuning ghrelin action in response to changing environmental conditions.

Keywords

GH; GHSR; LEAP2; VSG; bariatric surgery; blood glucose; caloric restriction; endogenous antagonist; ghrelin; hypoglycemia.

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