Sustained Weight Loss With Combined LEAP2 and Semaglutide Treatment in Mice.

UNLABELLED: The recent identification of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist and inverse agonist of the growth hormone secretagogue receptor (GHSR) has revived interest in targeting the ghrelin-GHSR pathway for obesity treatment. Here, we assessed the preclinical efficacy of treatment with a long-acting LEAP2 (LA-LEAP2) analog for weight loss and explored its potential as an adjunct to semaglutide to enhance weight reduction and mitigate weight regain. We found that LA-LEAP2 lowered body weight in obese mice, which was reflected in reduced energy intake and preserved energy expenditure. While not uniformly observed across all experiments, some studies demonstrated superior weight reduction with the combination of LA-LEAP2 and semaglutide compared with semaglutide monotherapy. Notably, the combination also attenuated weight regain more effectively than semaglutide alone. Importantly, no signs of discomfort or behavioral aversion were detected following LA-LEAP2 administration. Collectively, these data indicate that LEAP2 analogs have the potential to enhance the efficacy of glucagon-like peptide 1 receptor agonism and support durable weight loss. ARTICLE HIGHLIGHTS: Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous ghrelin receptor (GHSR) antagonist and inverse agonist and represents a novel strategy to modulate the GHSR system for treatment of cardiometabolic disease. A long-acting LEAP2 (LA-LEAP2) analog induces significant weight reduction in rodent models without causing aversion. LA-LEAP2-mediated weight loss is driven by decreased energy intake alongside preservation of energy expenditure during weight loss. Combined LA-LEAP2 and semaglutide therapy supports durable weight loss, addressing a critical gap in obesity treatment.