Regulation of adipose tissue microvascular function by IL19

项目摘要/摘要 超重和肥胖者不断扩大的内脏脂肪库(VAT)经历了 微循环缺氧性和白细胞异常浸润。免疫细胞渗入与缺氧 脂肪细胞引起全身性低度炎症，现在被认为是心血管疾病的原因。 和新陈代谢紊乱。因此，心脏代谢性疾病(高血压、肾脏疾病和 胰岛素抵抗)在美国不断增长的超重人口中变得流行起来。精准的 增重改变增值税微血管反应的机制尚不清楚。 此外，还没有确定增值税微血管反应受损是否是始动因素 心脏代谢功能障碍和疾病的原因。我们已经鉴定出一种新的脂肪因子IL-19，它表达于 人和小鼠的脂肪组织。IL-19是最近发现的一种新的Th2-IL 研究其在大血管疾病中的保护血管作用，如动脉粥样硬化和 缺血再灌注损伤。Co-Pi实验室获得的初步数据有力地表明，IL-19 调节饮食诱导肥胖脂肪组织微循环的动态平衡。因此， 这种双重研究应用的首要假设是，IL-19是一种独特的白细胞介素2 通过控制血管生成和炎症来维持心脏代谢动态平衡 增值税仓库的回应。这个项目的长期目标是：1)了解机制 IL-19通过其调节增值税中的血管和炎症；以及2)将这些机制联系起来 IL-19对全身胰岛素信号的微血管作用。为了实现这些目标，我们将利用淘汰赛 转基因小鼠技术以及生理、细胞、分子和生化技术。 我们预计，这项工作的结果将增进我们对综合机制的理解，这些机制 超重/肥胖者启动和维持VAT功能障碍及相关的心脏代谢紊乱 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.