Regulation of LEAP2 by insulin and glucagon in mice and humans

Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), exhibiting opposing effects on cell signaling, feeding, and hormonal secretion compared to ghrelin. However, despite an emerging interest in LEAP2’s physiology and pharmacology, its endocrine regulation remains unclear. Here, we show that plasma LEAP2 levels decrease significantly upon supraphysiological glucagon infusions during pancreatic somatostatin clamps in humans and that a hypercaloric diet and a sedentary lifestyle for two weeks impair this effect. Moreover, in patients with obesity and type 2 diabetes, plasma LEAP2 levels decrease significantly following glucagon infusion. Additionally, we find that postprandial upregulation of LEAP2 in mice is insulin-dependent. In the postprandial state, insulin receptor antagonism offsets the upregulation of hepatic Leap2expression and plasma LEAP2 levels. Finally, we show that insulin and glucagon receptor-expressing hepatocytes are the primary source of hepatic LEAP2 expression. This coincides with a putative enhancer-like signature bound by insulin- and glucagon-regulated transcription factors at the LEAP2 locus in the liver. Collectively, these findings implicate insulin and glucagonin the regulation of LEAP2 and highlight the need for further investigations into the endocrine mechanisms both upstream and downstream of LEAP2.