Hepatocyte androgen receptor in females mediates androgen-induced hepatocellular glucose mishandling and systemic insulin resistance

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in ARfl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (ARfl/fl) and LivARKO (ARfl/fl; Cre+/-) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Further, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR. ### Competing Interest Statement The authors have declared no competing interest. * AR : androgen receptor PCOS : polycystic ovary syndrome DHT : dihydrotestosterone CAH : congenital adrenal hyperplasia HA : hyperandrogenemia Con : control Veh : vehicle LH : luteinizing hormone Foxo1 : forkhead box protein O1 PEPCK : phosphoenolpyruvate carboxykinase G6Pase : glucose 6-phosphatase I.P . : intraperitoneal DPM : determine disintegrations per minute BMI : body mass index (BMI) GTT : glucose tolerance test ITT : insulin tolerance test PTT : pyruvate tolerance test GSIS : glucose stimulated insulin secretion HGP : hepatic glucose production GIR : glucose infusion rate.