Understanding the pathogenesis of elevated androgen induced metabolic dysfunction in females

了解雄激素升高引起的女性代谢功能障碍的发病机制

• 批准号: 9757802
• 负责人: Sheng Wu
• 金额: $ 40.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757802
• 关键词: Acute; Address; Androgen Receptor; Androgens; Body Composition; Body Weight; Cell Nucleus; Cell model; Cells; Congenital adrenal hyperplasia; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Data; Dendrimers; Development; Dose; FOXO1A gene; Female; Functional disorder; Gene Expression; Genes; Genetic; Genomics; Gestational Diabetes; Glucagon; Gluconeogenesis; Glucose; Healthcare Systems; Hepatic; Hepatocyte; Human; Hyperinsulinism; Impairment; In Vitro; Infertility; Insulin; Insulin Resistance; Insulin Signaling Pathway; Intervention; Knowledge; Lead; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phosphorylation; Play; Polycystic Ovary Syndrome; Prevention; Proteins; Proto-Oncogene Proteins c-akt; Receptor Signaling; Risk; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic Intervention; Tissues; Woman; glucose output; glucose production; hepatic gluconeogenesis; impaired glucose tolerance; improved; in vivo; innovation; insulin secretion; insulin signaling; molecular targeted therapies; mouse model; new therapeutic target; non-genomic; novel; novel therapeutic intervention; pancreatic juice; receptor; reproductive; transcription factor

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.

项目摘要 雄激素受体（AR）信号在雄激素诱导的代谢功能障碍中起着关键作用， 女性体内雄激素水平升高然而，肝脏中的AR如何导致代谢功能障碍， 雄激素过多，如多囊卵巢综合征（PCOS），是未知的。高雄激素血症是一种 PCOS的定义特征，并且通常伴有高胰岛素血症和肥胖， 识别雄激素信号传导在代谢功能障碍发展中的作用，而不是继发于受损 代谢功能因此，一个模型，可以隔离高雄激素血症的病理生理效应， 由肥胖引起的代谢变化是有道理的。我们观察到， 肝脏中的雄激素受体导致代谢功能受损。我们假设在一个 高雄激素水平的设置：1）雄激素/AR与AKT上游的蛋白质相互作用，以干扰 胰岛素信号传导，从而抑制叉头框O 1（FOXO 1）的磷酸化，导致增加 雄激素/AR调节cAMP-PKA（胰高血糖素）通路，增加cAMP活性 反应元件结合蛋白（CREB），并导致葡萄糖产量增加; 3）AR作为一种 调节Foxo 1和Creb基因表达的转录因子; 4）诱导 通过急性缺失AR可以纠正或改善代谢病理学， 干预策略。 我们将集中在病理生理雄激素水平的作用，通过AR在肝脏中。方法将使用 在雄激素升高的小鼠模型中，在肝脏中发育或急性AR基因缺失。AIM 1将专注于 通过定义肝细胞核AR在雄激素中的作用， 导致代谢功能障碍。目的2将确定是否需要核AR雄激素诱导 异源发生目标3将关注是否可以通过治疗雄激素过多相关的代谢功能障碍来改善雄激素水平。 通过急性肝AR缺失进行纠正或挽救。 这些目的将共同阐明AR在介导雄激素过多的致病作用中的作用， 导致女性代谢紊乱