High-fat diet (HFD) feeding induces systemic insulin resistance with pronounced sex- and tissue-specific differences; however, the role of hepatic androgen receptor (AR) signaling in this process remains unclear. The objective of this study was to determine whether hepatic AR differentially regulates insulin signaling and glucose metabolism during dietary stress in males and females. We hypothesized that loss of hepatic AR would protect against HFD-induced hepatic insulin resistance in a sex-dependent manner. To test this hypothesis, liver-specific AR knockout (LivARKO) and wild-type (WT) mice of both sexes were fed control or HFD for up to three months. Insulin signaling was assessed by insulin-stimulated Akt phosphorylation in liver, skeletal muscle, and white adipose tissue, and hepatic gluconeogenic gene expression was quantified by RT-qPCR. HFD impaired insulin-stimulated Akt phosphorylation across all tissues in WT mice, consistent with systemic insulin resistance. In females, LivARKO preserved hepatic insulin-stimulated Akt phosphorylation and significantly attenuated HFD-induced upregulation of phosphoenolpyruvate carboxykinase (Pck1) and glucose-6-phosphatase (G6pc), indicating protection from hepatic insulin resistance. This protection was not observed in skeletal muscle or adipose tissue. In contrast, male LivARKO mice exhibited no improvement in insulin signaling and showed further increases in hepatic Pck1 and G6pc expression compared with WT males. These findings demonstrate a sexually dimorphic role for hepatic AR in regulating insulin signaling and glucose metabolism during HFD feeding. Targeting hepatic AR signaling may represent a sex-specific strategy to mitigate diet-induced metabolic dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Stanley Andrisse (Fri,) studied this question.