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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：
10415165
负责人：
Sheng Wu
金额：
$ 53.65万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415165
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 androgen excess 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.

项目总结