1642-P: Metabolic Effects of Semaglutide and Resmetirom at Thermoneutrality in the Diet-Induced Obese Mouse

Introduction & Objective: Semaglutide (GLP-1 receptor agonist) is currently approved for the treatment of type 2 diabetes and obesity and in late-stage clinical development for MASH. Resmetirom, a selective THR-β agonist, is waiting for approval for MASH. The present study aimed to compare the effects of semaglutide and resmetirom monotherapy on metabolic endpoints at thermoneutrality in diet-induced obese (DIO) mice. Methods: Male C57BL/6J mice were fed a high-fat diet (60 kcal-% fat) for 32 weeks. Animals were acclimatized to thermoneutrality (28◦C) for 2 weeks prior to study start and randomized into treatment groups based on body weight and whole-body fat mass. DIO mice were administered vehicle, semaglutide (10 nmol/kg, SC, QD) or resmetirom (10 mg/kg, PO, QD) for 4 weeks. Chow-fed mice served as lean controls. Endpoints included body weight, food intake, whole-body fat/lean mass (echoMRI), plasma biochemistry and energy expenditure (EE) assessed using indirect calorimetry.

Results: Both compounds induced a sustained body weight loss (semaglutide, 25%; resmetirom, 13%) mainly driven by reduced food intake and fat mass. Semaglutide, but not resmetirom, also reduced lean mass. Only resmetirom enhanced EE after 1 and 4 weeks of treatment. The compounds equally improved hepatomegaly, fasting blood glucose and plasma triglycerides. Semaglutide improved hyperinsulinemia while only resmetirom normalized plasma cholesterol levels.

Conclusion: At thermoneutrality, semaglutide and resmetirom both improve metabolic outcomes in DIO mice. Notably, metabolic benefits of resmetirom treatment are associated with increased EE, highlighting the use of indirect calorimetry for profiling mechanism of action of drugs with therapeutic potential in obesity and MASH.