OR05-4 Androgen Induced Metabolic Dysfunction in Female Mice is Prevented by Deletion of Liver Androgen Receptor

Women with elevated androgen often exhibit hyperinsulinemia and insulin resistance. Many models have been created to produce metabolic dysfunction by manipulating androgen levels. Previously we reported that hyperandrogenemia produced by implantation of a DHT pellet may induce whole body insulin resistance through hepatic androgen receptor (AR) in vitro. Therefore, we conditionally disrupted the hepatic AR both developmentally (by breeding the albumin-CRE mouse (alb-CRE; liver-specific Cre expression) with ARfl/fl mice (LivARKO)) and acutely (by tail vein injection in ARfl/fl mice of adeno-associated virus with albumin promoter driven Cre vector (adLivARKO)). Impaired glucose tolerance, pyruvate tolerance, and insulin tolerance were prevented in both LivARKO-DHT and adLivARKO-DHT mice compared to control mice treated with DHT (ARfl/fl; cre-; Con-DHT) mice. Further, the glucose infusion rate is significantly reduced in LivARKO-DHT mice compared to Con-DHT mice as measured during hyperinsulinemia-euglycemia clamp suggesting improved insulin-induced glucose disposal. We observed that primary hepatocytes treated with DHT from both women and female mice showed reduced PI3K-pAKT and pFOXO1 activation by insulin, and increased ex vivo glucose production. LivARKO primary hepatocytes were resistant to DHT induced attenuated insulin signaling and increased gluconeogenesis (ex vivo) and this was confirmed in LivARKO in vivo. These data support a paradigm in which in females, elevated androgen disrupts metabolic function via hepatic AR.