| First Author | Andrisse S | Year | 2021 |
| Journal | FASEB J | Volume | 35 |
| Issue | 10 | Pages | e21921 |
| PubMed ID | 34547140 | Mgi Jnum | J:317717 |
| Mgi Id | MGI:6844968 | Doi | 10.1096/fj.202100961R |
| Citation | Andrisse S, et al. (2021) Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females. FASEB J 35(10):e21921 |
| abstractText | 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 AR(fl/fl) mice (adLivARKO). We observed normal metabolic function in littermate female Control (AR(fl/fl) ) and LivARKO (AR(fl/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). Furthermore, 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. |
