3069-LB: Human FcRn Transgenic Tg32 Mice Recapitulate the Metabolic Phenotype of Diet-Induced Obesity

Introduction and Objective: Diet-induced obesity (DIO) mouse models are widely used to study metabolic disease and evaluate therapies for obesity and type 2 diabetes. While C57BL/6J (B6) mice are the standard DIO model, human FcRn transgenic (Tg32) mice are increasingly used in therapeutic antibody development due to humanized neonatal Fc receptor expression. However, their susceptibility to diet-induced metabolic dysfunction remains poorly characterized. Methods: Male mice were randomized to diet groups at 6 weeks and monitored to 30 weeks. Cohorts included C57BL/6J (B6), human FcRn transgenic Tg32, and immunodeficient Tg32 scid mice. Mice were fed either a high-fat diet (60% kcal fat) or control diet (10% kcal fat). Body weight was measured weekly and non-fasted glucose monthly. GTTs were performed at 8, 16, 24, and 30 weeks. Serum biomarkers including glucose, lipids, insulin, leptin, and HbA1c were measured. Results: Body weight increased progressively in all high-fat diet groups; however, Tg32 scid mice showed significantly lower weight gain compared with B6 and Tg32 mice. After 12 weeks, mean weight gain was 24.8 ± 2.6 g in B6, 24.8 ± 4.7 g in Tg32, and 14.3 ± 2.2 g in Tg32 scid mice, representing ~42% lower gain in Tg32 scid mice, while B6 and Tg32 mice did not differ significantly. Non-fasted glucose levels were modestly elevated in B6 and Tg32 DIO mice relative to controls, consistent with the expected B6 DIO phenotype. Glucose intolerance emerged rapidly, with impaired clearance observed in all strains after two weeks of high-fat diet. Over time, B6 and Tg32 mice maintained consistent intolerance, while Tg32 scid mice showed greater variability in GTT responses. At 16 weeks, B6 DIO mice displayed pronounced metabolic changes, including increased HbA1c, serum glucose, cholesterol, HDL, triglycerides, insulin, and leptin. In contrast, Tg32 and Tg32 scid mice showed fewer significant alterations in these biomarkers. Conclusion: Tg32 mice replicate the B6 DIO metabolic phenotype and are suitable for metabolic studies with therapeutic antibodies. Disclosure A.Schile: None. A. : n/a. V.Yin: None.