LEAP2 Reduces Ad Libitum Food Intake and Attenuates Postprandial Glucose Excursions in Men With Obesity.

The naturally occurring peptide, liver-expressed antimicrobial peptide 2 (LEAP2), has gained interest as a ghrelin receptor antagonist. We previously reported reduced food intake and plasma glucose-lowering effects of LEAP2 infusion in lean healthy men; however, the effects of this competitive antagonist and inverse agonist of the ghrelin receptor in men with obesity have not been investigated. In the current study, 20 men with obesity were enrolled in a randomized, double-blind, placebo-controlled, crossover study comprising two experimental visits, each involving a ∼5-h intravenous infusion of LEAP2 (infusion rate 40 pmol/kg/min) or placebo during which a liquid mixed meal test and a subsequent ad libitum meal test were performed. The LEAP2 infusion resulted in a fivefold increase in plasma concentrations of LEAP2 compared with placebo. The infusion lowered postprandial plasma glucose levels and reduced ad libitum food intake by ∼12%. We conclude that a continuous intravenous LEAP2 infusion reduces glycemia and food intake in men with obesity, supporting further exploration of LEAP2's therapeutic potential in obesity and related metabolic conditions. ARTICLE HIGHLIGHTS: Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist and inverse agonist, reduces food intake and improves markers of dysmetabolism in preclinical studies and in lean men; however, the effects of LEAP2 in obesity are unknown. We investigated the effects of exogenous LEAP2 on ad libitum food intake and metabolic parameters in men with obesity. We found that LEAP2 reduces ad libitum food intake and reduces postprandial plasma glucose concentration, revitalizing the ghrelin receptor as a potential target in the treatment of obesity and its related conditions.