2504-P: Androgen Excess Uncouples Circulating and Hepatic Lipid Homeostasis in Females on a High-Calorie Diet

Introduction and Objective: Androgen excess (AE), a common feature of polycystic ovary syndrome, congenital adrenal hyperplasia, and gender-affirming hormone therapy, is a known driver of insulin resistance (IR), yet how AE influences hepatic lipid homeostasis is not well understood. We aimed to investigate how AE-IR with comparable body weight conditions, regulates hepatic lipid metabolism under both a regular and western diet conditions. . Methods: Adult female mice will be implanted with a continuous release dihydrotestosterone (DHT) pellet and maintained on either a regular chow diet or a Western diet (WD). Mice with or without DHT and with or without growth hormone (GH) infusion will be studied in control and hepatocyte specific androgen receptor knockout mice. Energy expenditure will be assessed using CLAMS, and glucose homeostasis will be evaluated. Liver phenotyping will include histological analysis, RNA sequencing, proteomics, Western blotting, and ELISA. Results: In age and weight matched female mice, DHT protected against metabolic dysfunction associated steatotic liver disease (MASLD) under western diet by reducing hepatic triglyceride (TG) accumulation, while simultaneously exacerbating systemic hypertriglyceridemia and IR, without altering hepatic insulin-Akt signaling. This protection against MASLD occurred independently of hepatic androgen receptor (AR) signaling. Multi-omics profiling revealed that DHT. DHT enhanced hepatic STAT5 activation, suppressed expression of the fatty acid (FA) transporter Cd36, and reduced hepatic FA uptake, while increasing very low density lipoprotein triglyceride (VLDL-TG) secretion. Continuous GH infusion, which mimics the female GH secretion pattern, reversed these effects by attenuating STAT5 activation and restoring Cd36 expression. Conclusion: Together, these findings identify a GH dependent, hepatic AR and insulin independent pathway through which AE regulates hepatic lipid homeostasis. Disclosure S. Wu: None. Funding R01- HD09551201A1