LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor

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. [Display omitted] •LEAP2 identified as an endogenous peptide antagonist of the ghrelin receptor•LEAP2 modulates ghrelin function in response to physiological conditions•Overexpressing LEAP2 in mice phenocopies ghrelin deficiency•Suppressing LEAP2 using function-blocking antibodies enhances ghrelin action Ghrelin maintains blood glucose levels in the face of starvation. Ge et al. identify LEAP2 as an endogenous antagonist of the ghrelin receptor that modulates ghrelin function in response to nutrient status, such as fasting. Increasing or suppressing LEAP2 leads to corresponding counter-regulation of ghrelin action in vivo.