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.

中文翻译：

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LEAP2是Ghrelin受体的内源性拮抗剂。

Ghrelin是胃分泌的食欲刺激激素，被发现是生长激素促分泌素受体（GHSR）的配体。ghrelin通过GHSR刺激生长激素（GH）的分泌，这一功能已演变为预防饥饿引起的低血糖症。尽管已经详细描述了生长激素释放肽介导的生物学，但对生长激素释放肽作用的调节知之甚少。在这里，我们报告发现肝脏表达的抗菌肽2（LEAP2）作为GHSR的内源性拮抗剂。LEAP2在肝脏和小肠中产生，禁食可抑制其分泌。LEAP2完全抑制ghrelin激活GHSR，并阻断ghrelin在体内的主要作用，包括食物摄入，GH释放以及在长期热量限制期间维持可行的葡萄糖水平。相比之下，阻断内源性LEAP2功能的中和抗体可增强体内生长素释放肽的作用。我们的发现揭示了一种机制，可以根据环境条件的变化微调生长素释放肽的作用。