Liver-enriched antimicrobial peptide 2(Gentofte Hospital)

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.

Obesity is a global public health challenge intimately linked to cardiometabolic complications. Although current anti-obesity medications can produce substantial and rapid weight loss, their discontinuation often results in rapid weight regain, underscoring the urgent need for therapies that support long-term weight loss maintenance. The ghrelin receptor system, comprising the hormone ghrelin and its receptor growth hormone secretagogue receptor 1a (GHSR1a), has long been a target for appetite regulation, but decades of drug development have yielded limited clinical success. The recent discovery of liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous GHSR1a antagonist and inverse agonist, has reignited interest in this pathway. LEAP2 suppresses appetite in both rodents and humans, and optimized analogs have shown modest but promising metabolic effects in preclinical models. Although less potent than currently leading agents, LEAP2-based therapies may offer value as adjunct treatments, particularly for sustaining weight loss. This review explores the evolving therapeutic potential of the GHSR1a pathway, with a particular focus on LEAP2 as a novel strategy for treating obesity and associated cardiometabolic disorders.