Regulation of adipose tissue microvascular function by IL19

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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.