Androgen excess uncouples circulating and hepatic lipid homeostasis in females on a high-calorie diet.

Androgen excess is a common feature of polycystic ovary syndrome, congenital adrenal hyperplasia, gender affirming hormone therapy and is a known driver of disrupted glucose homeostasis. However, its impact on hepatic lipid regulation remains poorly understood with conflicting results. In age and weight matched female mice, dihydrotestosterone (DHT) treatment under a regular chow diet did not alter hepatic or circulating lipid levels. In contrast, under a western diet, DHT protected against metabolic dysfunction-associated steatotic liver disease by reducing hepatic triglyceride (TG) accumulation, even as it exacerbated systemic hypertriglyceridemia. These effects occurred without changes in hepatic insulin-Akt signaling and were independent of hepatic androgen receptor signaling. Multiomics profiling revealed that DHT reprogrammed hepatic transcription toward a male like pattern driven by pulsatile growth hormone (GH)-STAT5 signaling. DHT enhanced hepatic STAT5 activation, suppressed expression of the fatty acid (FA) transporter Cd36, and reduced hepatic FA uptake, even in the presence of elevated circulating free fatty acid. DHT also increased VLDL-TG secretion and altered hepatic FA composition. Continuous GH infusion, which mimics the female GH secretion pattern, reversed these effects by attenuating STAT5 activation and restoring Cd36 expression. Together, these findings identify a GH-dependent, hepatic androgen receptor -independent pathway through which androgen excess shapes hepatic lipid homeostasis. They further show that DHT elicits divergent systemic effects, with impaired glucose homeostasis and enhanced lipolysis occurring alongside reduced hepatic lipid accumulation but increased TG secretion.