Metabolic Assessment of Semaglutide (a GLP-1R Agonist) and Tirzepatide (a GLP-1R/GIPR Coagonist) in Diet-Induced Obese (DIO) Mice

Introduction and Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) effectively manage Type 2 Diabetes Mellitus by improving glucose levels, β-cell function, and weight reduction. This study evaluated body composition changes after incretin treatments and withdrawal in a diet-induced obese mouse model. Methods: Adult male C57BL/6J mice JR#380050) were fed a high-fat diet (60% kcal from fat, D12492) for 14 weeks to induce obesity and then randomized (n=18/group) into Vehicle (Saline), Semaglutide (10 nmol/kg), and Tirzepatide (10 nmol/kg), all administered s.c once daily for 4 weeks. Body weight, food intake, and body composition were monitored, with glucose and insulin tolerance tests, along with microCT imaging. The study included an additional 2-week drug withdrawal period on a high-fat diet. Results: Vehicle-treated mice showed minimal weight change, while Semaglutide reduced body weight by ~7%, and Tirzepatide induced a ~30% reduction. Both Semaglutide and Tirzepatide displayed acute drop in food intake. Fat mass was decreased 16% with Semaglutide at 4 weeks, while Tirzepatide achieved reductions of 62%. Lean mass increased by 2.5% in Vehicle-treated mice but decreased by 1% and 7.8% with Semaglutide and Tirzepatide, respectively. Both treatments improved glucose tolerance and insulin sensitivity, with Tirzepatide showing greater effects (p<0.0001 vs. p<0.01 for Semaglutide). MicroCT imaging confirmed reductions in subcutaneous and visceral fat after Semaglutide and Tirzepatide treatments. Following a 2-week withdrawal, Semaglutide and Tirzepatide treatments resulted in ~5% and 20% weight gains, respectively, due to increased food intake and fat/lean mass gains. Conclusion: Incretin treatments markedly improved glucose tolerance, and insulin sensitivity in DIO mice, with Tirzepatide demonstrating greater effectiveness in reducing subcutaneous and visceral adiposity. Disclosure: S. Olkkola: None. K.A. Eschete: None. J. Swagel: None. A..: None.