Liver androgen receptor knockout protects female mice from high fat diet-induced insulin resistance.

High-fat diet (HFD) feeding induces reduced insulin-stimulated AKT phosphorylation with notable sex- and tissue-specific variability, yet the contribution of hepatic androgen receptor (AR) signaling to these effects remains unclear. To investigate the role of hepatic AR in metabolic regulation under dietary stress, liver-specific AR knockout (LivARKO) and wild-type (WT) mice of both sexes were fed control or HFD diets for up to 3 months. HFD impaired insulin-stimulated Akt phosphorylation across liver, skeletal muscle, and white adipose tissue in WT mice. In females, LivARKO preserved hepatic insulin sensitivity and attenuated HFD-induced induction of gluconeogenic genes Pck1 and G6pc, indicating protection from hepatic insulin resistance. This effect was not observed in skeletal muscle or adipose tissue. In contrast, male LivARKO mice showed no protection from HFD-induced insulin resistance and exhibited further upregulation of 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 offer a sex-specific strategy for mitigating diet-induced metabolic dysfunction and improving metabolic health outcomes.