The Role of Androgens in Obesity Induced Meta-Inflammation

项目概要/摘要： 由于肥胖引起的疾病的高患病率，肥胖是社会的重大负担。识别 肥胖个体有患代谢和心血管疾病的风险是一个必要的步骤， 个性化的治疗策略。男性是代谢和心血管疾病的一个强有力的危险因素 而慢性炎症的测量则将肥胖与疾病风险紧密联系起来。代谢的性别差异 疾病生理学、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，我们一直在调查的中心概念，性别差异，代谢 疾病相关性炎症（继发性炎症）导致糖尿病的风险差异， 肥胖的男女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，有一个夸大的骨髓炎症反应， 高脂肪饮食，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，去势的雄性小鼠葡萄糖代谢得到改善，脂肪组织减少， 尽管与完整的男性对照组相比，肥胖增加，但仍然存在炎症。基于这些发现，我们 将研究雄激素通过以下方式促进炎症和代谢受损的假设： 增强巨噬细胞活化和骨髓生成。我们将通过完成两个目标来测试我们的假设： 1)为了确定雄激素依赖性脂肪组织巨噬细胞活化的机制， 胰岛素抵抗与肥胖目的2）探讨雄激素受体介导的细胞凋亡机制。 骨髓祖细胞和单核细胞中的信号传导介导肥胖诱导的炎症。 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点， 代谢诱导炎症的性别差异。这个项目有可能缩小我们在这方面的关键差距。 了解性别差异，并采取创新的逐步方法来了解雄激素的影响 对肥胖期间骨髓细胞产生、单核细胞募集和巨噬细胞极化的影响。

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.