Regulation of adipose tissue microvascular function by IL19

项目总结/摘要 超重和肥胖个体的内脏脂肪库（VAT）不断扩大， 微循环缺氧和白细胞异常浸润。免疫细胞浸润和缺氧 脂肪细胞引起系统性低度炎症，现在认为是心血管疾病的病因 和代谢紊乱。因此，心脏代谢疾病（高血压、肾脏疾病和 胰岛素抵抗）在美国不断增长的超重人群中变得流行。的精确 体重增加改变VAT微血管反应的机制仍知之甚少。 此外，还没有确定VAT的微血管反应受损是否是启动 心脏代谢功能障碍和疾病的原因。我们已经鉴定了一种新的脂肪因子IL-19，表达于 人类和小鼠的脂肪组织。IL-19是新近发现的一种Th 2型白细胞介素， 研究其在动脉粥样硬化等大血管疾病中的血管保护作用， 缺血再灌注损伤在Co-PI实验室获得的初步数据强烈表明，IL-19 调节饮食诱导的肥胖症中脂肪组织微循环的稳态。因此 这一双重研究者应用的首要假设是IL-19是一种独特的白细胞介素 通过控制血管生成和炎症反应来维持心脏代谢的稳态 增值税仓库的答复。本项目的长期目标是：1）了解机制 IL-19通过其调节VAT中的血管分布和炎症;以及2）将这些机制与 IL-19对全身胰岛素信号传导的微血管作用。为了实现这些目标，我们将利用淘汰赛 以及转基因小鼠技术沿着生理学、细胞学、分子学和生物化学技术。 我们预计，这项工作的结果将增进我们对综合机制的了解， 启动和维持超重/肥胖患者的VAT功能障碍和相关心脏代谢紊乱 有机体

PROJECT SUMMARY / ABSTRACT The expanding visceral fat depots (VAT) of overweight and obese individuals experience dysfunction of the microcirculation with hypoxia and abnormal infiltration of leukocytes. Infiltrating immune cells and hypoxic adipocytes cause a systemic low-grade inflammation that is considered now causative of cardiovascular disease and metabolic disorders. Thus, the incidence of cardiometabolic disorders (hypertension, kidney disease, and insulin resistance) are becoming epidemic in the ever-growing overweight population of the USA. The precise mechanisms by which weight gain alters microvascular responses in VAT remain poorly understood. Furthermore, it has not been determined whether impaired microvascular responses of VAT are the initiating cause of cardiometabolic dysfunction and disease. We have identified a novel adipokine, IL-19, expressed in the adipose tissue of humans and mice. IL-19 is a newly discovered Th2-interleukin which has been recently studied for its protective vascular effects in the setting of large vessels disease, such as atherosclerosis and ischemia reperfusion injury. Preliminary data obtained in the Co-PI's laboratories strongly suggest that IL-19 regulate the homeostasis of adipose tissue microcirculation in diet-induced obesity. Accordingly, the overarching hypothesis of this dual-investigator application is that IL-19 is a unique interleukin that maintains cardiometabolic homeostasis by controlling angiogenesis and inflammatory responses in VAT depots. The long-term goals of this project are: 1) to understand the mechanisms through which IL-19 regulates vascularity and inflammation in VAT; and 2) to mechanistically correlate these microvascular actions of IL-19 to whole-body insulin signaling. Toward these goals, we will utilize knockout and transgenic mouse technology along with physiological, cellular, molecular, and biochemical techniques. We anticipate that the results of this work will advance our understanding of the integrated mechanisms that initiate and maintain VAT dysfunction and related cardiometabolic disorders in the overweight/obese organism.