Sustained Weight Loss With Combined LEAP2 and Semaglutide Treatment in Mice

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.