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.

中文翻译：

---

雄激素诱导的胰岛素抵抗通过女性肝脏雄激素受体的缺失得到改善

雄激素过多症是育龄妇女最常见的内分泌疾病之一，影响多达 20% 的人群。雄激素升高的女性经常表现出高胰岛素血症和胰岛素抵抗。雄激素升高如何影响代谢功能的机制尚不清楚。双氢睾酮 (DHT) 治疗的雌性小鼠模型中的高雄激素血症可能通过激活肝雄激素受体 (AR) 诱导全身胰岛素抵抗。我们研究了肝细胞 AR 在高雄激素血症诱导的代谢功能障碍中的作用，通过基于动物、细胞和临床的方法使用几种方法来消除肝 AR。^fl/fl小鼠 (adLivARKO)。我们在同窝雌性对照 (AR ^fl/fl ) 和 LivARKO (AR ^fl/fl ; Cre ^+/-） 老鼠。在慢性 DHT 治疗后，用 DHT (Con-DHT) 治疗的雌性对照小鼠出现葡萄糖耐量、丙酮酸耐量和胰岛素耐受性受损，而在用 DHT (LivARKO-DHT) 治疗的 LivARKO 小鼠中未观察到。此外，在正常血糖高胰岛素钳夹期间，与 Con-DHT 小鼠相比，LivARKO-DHT 小鼠的葡萄糖输注速率有所提高。来自 LivARKO 的肝脏、来自 LivARKO 的原代肝细胞和 adLivARKO 小鼠免受 DHT 诱导的胰岛素抵抗和增加的糖异生。这些数据支持这样一种范式，其中女性体内雄激素升高通过肝脏 AR 破坏代谢功能，并且通过删除肝脏 AR 来恢复胰岛素敏感性。