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

• 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
• 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' 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

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.

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