2495-P: Testosterone Deficiency Promotes Diet-Induced Hepatic Steatosis in Mice

Introduction and Objective: Lifestyle factors and increased consumption of high-fat diets largely contribute to the development of obesity, insulin resistance, type 2 diabetes (T2DM), and cardiovascular diseases. One major consequence of this lifestyle is non-alcoholic fatty liver disease (NAFLD), which affects approximately 30% of adults and up to 10% of children in developed countries. Obesity is also a leading cause of reduced testosterone levels in men, affecting 20-40% of obese individuals compared to only 4-5% in the general male population. This study aimed to evaluate the effects of testosterone on metabolic regulation in male mice. Methods: Male C57BL/6J mice were chemically castrated using Degarelix (DGX), with or without testosterone replacement therapy (TRT), and fed either a standard diet (SD) or a high-fat diet (HFD; 45% kcal from fat) for 8 weeks, forming six experimental groups. Results: Low testosterone levels (DGX+HFD) decreased lean mass without altering total body weight or fat mass and did not affect glucose tolerance; however, they promoted hepatic triglyceride accumulation, reduced plasma cholesterol, and impaired VLDL-TG export. Additionally, testosterone deficiency attenuated HFD-induced fasting hyperinsulinemia but modestly elevated serum AST and ALT levels. TRT reversed these effects, restoring lipid export, fasting insulin, and lean-to-fat ratio, although further increasing hepatic enzyme levels. Conclusion: In conclusion, androgenic hormones play a key role in hepatic lipid metabolism and the insulin response to obesity. Low testosterone mitigates hyperinsulinemia but exacerbates hepatic lipid accumulation, warranting further investigation into the underlying mechanisms. Disclosure F. Sucupira: None. A. Goncalves da Cruz: None.