Introduction and Objective: Mouse models of obesity exhibit heterogeneity in metabolic flexibility, with diet-induced obesity (DIO) mice showing greater adaptability in energy balance regulation, while monogenic obesity models have impaired compensatory mechanisms due to genetic mutations. In this study, we assessed the metabolic impacts of mono, dual, and triple GLP-1 agonists on a monogenic (db/db) mouse model of obesity and type-2 diabetes.Methods: Adult male B6.BKS(D)-Leprdb/J mice (6 weeks old) were randomized into four treatment groups (n=20/group): Vehicle (PBS), Semaglutide (10 nmol/kg), Tirzepatide (10 nmol/kg), and Retatrutide (10 nmol/kg). All treatments were administered subcutaneously once daily for four weeks. Metabolic assessments included measurements of body weight, food intake, fat, and lean mass, along with glucose tolerance testing, microCT imaging, and proteomic analysis.Results: At randomization, Leprdb/db mice had an average body weight of 37.2 ± 1.2 g. Over the treatment period, vehicle-treated mice exhibited a 23% increase in body weight, whereas Semaglutide, Tirzepatide, and Retatrutide treatment mitigated weight gain, resulting in increases of 20%, 14.2%, and 14.3%, respectively. The tirzepatide treatment group exhibited the greatest reduction in food intake. Blood glucose levels were significantly reduced in the Tirzepatide-treated group (Vehicle: 297.6 mg/dL vs. Tirzepatide: 124.3 mg/dL, p<0.05). During the glucose tolerance test (GTT), both Semaglutide (p<0.05) and Tirzepatide (p<0.001) exhibited enhanced glucose clearance compared to the vehicle-treated group. Fat mass was reduced by 14.3% with Semaglutide, 17.2% with Tirzepatide, and 17.5% with Retatrutide from baseline. Conversely, lean mass increased by 3.2% in the vehicle group, 6.9% with Semaglutide, 1.75% with Tirzepatide, and 0.5% with Retatrutide.Conclusion: Overall, Tirzepatide demonstrated the most pronounced metabolic benefits in the monogenic model of obesity coupled with type-2 diabetes.
K.A. Eschete: None. S. Olkkola: None. J. Swagel: None. A. Dunn: None. N. Bethur: None. H. Kaur: None. T. Stodola: None. B. Hoffmann: None. K. O’Connell: None. V. Yin: None. A. .: None.
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