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：
9919557
负责人：
Kanakadurga Singer
金额：
$ 44.6万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919557
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 sensitive base cell type cellular targeting design diabetes risk disorder risk glucose metabolism glucose tolerance improved innovation insight knockout animal macrophage male men monocyte myeloid cell development novel novel marker 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，肥胖是社会的重大负担。识别哪些肥胖个体有代谢和心血管疾病的风险是个性化治疗策略。男性是代谢和心血管疾病的强大危险因素慢性炎症的措施将肥胖与疾病风险紧密联系在一起。代谢的性别差异疾病生理，表现和治疗反应可能与不同的炎症反应有关男女。因此，我们一直在研究代谢性别差异的中心概念疾病相关的炎症（元炎）有助于糖尿病的差异风险肥胖的男人和女人。该模型的科学前提是基于现有的免疫学文献我们认为雄性小鼠而不是女性的骨髓炎症反应夸大了高脂饮食可促进脂肪组织巨噬细胞的积累和激活。我们的初步研究还表明，cast割的雄性小鼠改善了葡萄糖代谢并减少了脂肪组织与完整的男性对照相比，炎症尽管肥胖增加了。基于这些发现，我们将研究以下假设，即雄激素会促进元炎和损害的代谢。增强巨噬细胞的激活和骨髓病。我们将通过完成两个目标来检验我们的假设：目标 1）确定依赖雄激素的脂肪组织巨噬细胞激活和肥胖症中的胰岛素抵抗。目标2）确定雄激素受体的机制髓样祖细胞和单核细胞中的信号传导介导肥胖引起的炎症。完成我们的目标将确定肥胖期间雄激素活性的细胞和分子靶标代谢引起的炎症的性别差异。该项目有可能弥合我们的关键差距了解性别差异，并采用创新的逐步方法来了解雄激素的影响在肥胖期间，骨髓细胞的产生，单核细胞募集和巨噬细胞极化。