Understanding the pathogenesis of elevated androgen induced metabolic dysfunction in females

项目摘要 雄激素受体(AR)信号在雄激素诱导的状态代谢功能障碍中起关键作用 女性体内雄激素升高的可能性。然而，肝脏中的AR如何在高血压状态下导致代谢障碍 雄激素过多，如多囊卵巢综合征(PCOS)，尚不清楚。高雄激素血症是 多囊卵巢综合征的定义特征，并经常伴随高胰岛素血症和肥胖，使其难以 识别雄激素信号在不继发于受损的代谢功能障碍发展中的作用 新陈代谢功能。因此，一种能够分离高雄激素血症病理生理效应的模型 肥胖引起的新陈代谢变化是合理的。我们观察到雄激素升高通过 肝脏中的雄激素受体导致代谢功能受损。我们假设在一个 设置高雄激素水平：1)雄激素/AR与AKT上游蛋白相互作用干扰 胰岛素信号转导，从而抑制叉头盒O1(FOXO1)的磷酸化，导致 2)雄激素/AR调节cAMP-PKA(胰高血糖素)途径，增加cAMP活性 反应元件结合蛋白(CREB)，并导致葡萄糖产生增加；3)AR作为一种 转录因子调节Foxo1和Creb基因表达促进糖异生；4)诱导 AR的急性缺失可以纠正或改善代谢病理，从而为治疗指明了方向 干预性策略。 我们将专注于通过AR在肝脏中发挥作用的病理生理雄激素水平的作用。方法将使用 雄激素水平升高小鼠肝脏AR基因缺失的研究。Aim1将专注于 通过确定肝细胞核外AR在雄激素中的作用来研究肝脏(小鼠和人肝细胞) 导致代谢功能障碍。目标2将确定雄激素诱导是否需要核AR 糖异生作用。目标3将集中在与雄激素过多相关的代谢功能障碍是否可以 通过急性删除肝脏AR来纠正或挽救。 结合这些目标，将阐明AR在介导雄激素过多的致病作用中的作用。 导致女性代谢功能障碍。

Project Summary Androgen receptor (AR) signaling plays a crucial role in androgen induced metabolic dysfunction in states of elevated androgen in females. However, how AR in the liver contribute to metabolic dysfunction in states of androgen excess, such as in polycystic ovary syndrome (PCOS), is unknown. Hyperandrogenemia is one of the defining features of PCOS, and is often accompanied by hyperinsulinemia and obesity making it difficult to discern the role of androgen signaling in the development of metabolic dysfunction not secondary to impaired metabolic function. Therefore, a model that can isolate the pathophysiological effects of hyperandrogenemia from metabolic changes resulting from obesity is warranted. We observed that elevated androgen through androgen receptor in the liver contributes to impaired metabolic function. We hypothesized that in a setting of high androgen levels: 1) androgen/AR interacts with proteins upstream of AKT to interfere with insulin signaling, thus inhibiting the phosphorylation of forkhead box O1 (FOXO1), leading to increased gluconeogenesis; 2) androgen/AR regulates the cAMP-PKA (glucagon) pathway to increase activity of cAMP response element binding protein (CREB), and leading to increased glucose production; 3) AR acts as a transcription factor regulating Foxo1 and Creb gene expression to increase gluconeogenesis; 4) induced metabolic pathology can be corrected or improved by acute deletion of AR thus pointing the way to therapeutic interventional strategies. We will focus on the role of pathophysiological androgen levels acting via AR in the liver. Approaches will use genetic deletion of AR developmentally or acutely in liver in elevated androgen mouse models. Aim1 will focus on the liver (mouse and human hepatocytes) by defining the role of hepatocyte extranuclear AR in androgen induced metabolic dysfunction. Aim 2 will determine whether nuclear AR is required for androgen induced gluconeogenesis. Aim 3 will focus on whether metabolic dysfunction associated with androgen excess can be corrected or rescued by acute deletion of hepatic AR. Together these Aims will elucidate the role of AR in mediating the pathogenic effects of androgen excess in contributing to female metabolic dysfunction.