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

基本信息

批准号：
10214653
负责人：
Sheng Wu
金额：
$ 57.63万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10214653
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 Hyperandrogenemia 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

项目摘要

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.

项目概要雄激素受体 (AR) 信号在雄激素诱导的代谢功能障碍中起着至关重要的作用女性雄激素升高。然而，肝脏中的 AR 如何在以下状态下导致代谢功能障碍：雄激素过多，例如多囊卵巢综合症（PCOS），尚不清楚。高雄激素血症是其中之一 PCOS 的定义特征，通常伴有高胰岛素血症和肥胖，因此很难辨别雄激素信号传导在代谢功能障碍发展中的作用，而不是继发于受损的代谢功能障碍代谢功能。因此，可以分离高雄激素血症的病理生理效应的模型肥胖引起的代谢变化是有道理的。我们观察到雄激素水平升高肝脏中的雄激素受体会导致代谢功能受损。我们假设在一个设置高雄激素水平：1) 雄激素/AR 与 AKT 上游的蛋白质相互作用，干扰胰岛素信号传导，从而抑制叉头盒 O1 (FOXO1) 的磷酸化，导致糖异生； 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），并导致葡萄糖产量增加； 3）AR充当转录因子调节 Foxo1 和 Creb 基因表达以增加糖异生； 4）诱发 AR的急性缺失可以纠正或改善代谢病理学，从而为治疗指明了道路干预策略。我们将重点关注通过 AR 在肝脏中发挥作用的病理生理雄激素水平的作用。将使用的方法在雄激素升高的小鼠模型中，AR在肝脏中发育或急性地发生遗传缺失。 Aim1 将聚焦通过定义肝细胞核外 AR 在雄激素中的作用对肝脏（小鼠和人类肝细胞）的影响诱发代谢功能障碍。目标 2 将确定雄激素诱导是否需要核 AR 糖异生。目标 3 将重点关注与雄激素过多相关的代谢功能障碍是否可以通过通过急性删除肝脏 AR 来纠正或挽救。这些目标将共同阐明 AR 在介导雄激素过多的致病作用中的作用。导致女性代谢功能障碍。