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Sustained Weight Loss With Combined LEAP2 and Semaglutide Treatment in Mice
Stephanie K Holm1, Valdemar B I Johansen1, Pablo Ranea-Robles1,2,3,4
1Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Diabetes
|July 1, 2025
Summary
Liver-expressed antimicrobial peptide 2 (LEAP2) effectively reduces weight in rodent models by decreasing energy intake. Combined with semaglutide, long-acting LEAP2 offers a promising strategy for durable obesity treatment.
Area of Science:
- Endocrinology
- Metabolic disease research
- Peptide therapeutics
Background:
- The ghrelin receptor (GHSR) system plays a key role in regulating energy balance.
- Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous antagonist and inverse agonist of GHSR.
- Modulating the GHSR system presents a novel therapeutic strategy for cardiometabolic diseases.
Purpose of the Study:
- To evaluate the efficacy of a long-acting LEAP2 (LA-LEAP2) analog in promoting weight reduction.
- To investigate the mechanisms underlying LA-LEAP2-mediated weight loss.
- To assess the potential of combining LA-LEAP2 with semaglutide for enhanced obesity treatment.
Main Methods:
- Administration of a long-acting LEAP2 analog in rodent models.
- Assessment of body weight changes, energy intake, and energy expenditure.
- Evaluation of combined LA-LEAP2 and semaglutide therapy.
Main Results:
- LA-LEAP2 analog induced significant weight reduction in rodent models without causing aversion.
- Weight loss was attributed to decreased energy intake while preserving energy expenditure.
- Combination therapy with LA-LEAP2 and semaglutide supported durable weight loss.
Conclusions:
- Long-acting LEAP2 is a viable therapeutic candidate for weight management.
- LA-LEAP2 modulates energy balance through appetite suppression and metabolic preservation.
- Combined LA-LEAP2 and semaglutide therapy addresses a critical need for effective and durable obesity treatments.
