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The Role of Androgens in Obesity Induced Meta-Inflammation

雄激素在肥胖引起的元炎症中的作用

基本信息

批准号：
10398116
负责人：
Kanakadurga Singer
金额：
$ 43.21万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2018-07-11 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10398116
关键词：
Address Adipose tissue Adult Androgen Antagonists Androgen Receptor Androgenization Androgens Animals Attenuated Bone Marrow Bone Marrow Transplantation Cardiovascular Diseases Castration Chronic Clinical Data Dependence Development Diabetes Mellitus Disease Female Flutamide Functional disorder Future Gender Role Generations Genetic Models Goals Gonadal Steroid Hormones Heart Diseases Hematopoietic Hematopoietic stem cells High Fat Diet High Prevalence Hormones ITGAX gene Immunology Impairment In Vitro Individual Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Investigation Knowledge Leukocytes Link Literature Macrophage Activation Marrow Measures Mediating Mediator of activation protein Men&apos s Role Metabolic Metabolic Diseases Metabolism Modeling Molecular Target Mus Myelogenous Myeloid Cells Myeloid Progenitor Cells Myelopoiesis Natural Immunity Obesity Pathway interactions Physiology Play Population Premenopause Production Receptor Signaling Research Risk Risk Factors Role Saturated Fatty Acids Sex Differences Signal Transduction Societies Steatohepatitis Testing Tissues Transplantation Woman Work androgen excess androgen sensitive base cell type cellular targeting design diabetes risk diet-induced obesity disorder risk glucose metabolism glucose tolerance improved innovation insight knockout animal macrophage male men monocyte myeloid cell development novel novel marker obese person personalized medicine postnatal progenitor recruit response sex treatment response treatment strategy

项目摘要

Project Summary/Abstract: Obesity is a significant burden on society due to the high prevalence of obesity-induced diseases. Identifying which obese individuals are at risk for metabolic and cardiovascular disease is a necessary step for personalized treatment strategies. Male sex is a strong risk factor for metabolic and cardiovascular disease and measures of chronic inflammation strongly link obesity to disease risk. Sex differences in metabolic disease physiology, presentation, and treatment responses may relate to different inflammatory responses in men and women. Therefore, we have been investigating the central concept that sex differences in metabolic disease associated inflammation (meta-inflammation) contribute to the differential risk for diabetes between obese men and women. The scientific premise for this model is based on the existing immunology literature and our observations that male mice, but not females, have an exaggerated myeloid inflammatory response to high fat diets that promotes the accumulation and activation of adipose tissue macrophages. Our preliminary studies also show that castrated male mice have improved glucose metabolism and reduced adipose tissue inflammation despite having increased adiposity compared to intact male controls. Based on these findings, we will investigate the hypothesis that androgens promote meta-inflammation and impaired metabolism by enhancing macrophage activation and myelopoiesis. We will test our hypothesis by completing two aims: Aim 1) To determine the mechanisms of androgen dependent adipose tissue macrophage activation and insulin resistance in obesity. Aim 2) To determine the mechanism by which androgen receptor signaling in myeloid progenitor cells and monocytes mediates obesity-induced inflammation. Completing our aims will identify the cellular and molecular targets for androgen activity during obesity, leading to sex differences in metabolic-induced inflammation. This project has the potential to close critical gaps in our understanding of sex-differences and takes an innovative step-wise approach to understand androgen effects on myeloid cell production, monocyte recruitment, and macrophage polarization during obesity.

项目摘要/摘要：由于肥胖引起的疾病的高流行率，肥胖是社会的一个重大负担。识别哪些肥胖个体有患代谢和心血管疾病的风险是个性化治疗策略。男性是新陈代谢和心血管疾病的强烈危险因素慢性炎症的衡量标准将肥胖与疾病风险紧密联系在一起。新陈代谢的性别差异疾病的生理、表现和治疗反应可能与不同的炎症反应有关男人和女人。因此，我们一直在研究这样一个中心概念，即新陈代谢中的性别差异与疾病相关的炎症(化炎症)有助于区分糖尿病和肥胖的男人和女人。该模型的科学前提是基于现有的免疫学文献。我们观察到，雄性小鼠，而不是雌性小鼠，对促进脂肪组织巨噬细胞积聚和激活的高脂肪饮食。我们的预赛研究还表明，去势的雄性小鼠改善了葡萄糖代谢，减少了脂肪组织尽管与正常男性对照组相比，肥胖程度增加了，但仍存在炎症。基于这些发现，我们将调查雄激素促进化生炎症和新陈代谢受损的假说促进巨噬细胞活化和骨髓生成。我们将通过完成两个目标来验证我们的假设：目标 1)探讨雄激素依赖性脂肪组织巨噬细胞活化的机制肥胖中的胰岛素抵抗。目的2)确定雄激素受体的作用机制髓系祖细胞和单核细胞中的信号介导肥胖诱导的炎症。完成我们的目标将确定肥胖症期间雄激素活性的细胞和分子靶点，代谢性炎症中的性别差异。该项目有可能弥合我们的关键差距了解性别差异，并采取创新的循序渐进的方法来了解雄激素的影响肥胖期间髓系细胞产生、单核细胞募集和巨噬细胞极化的影响。