Type 2 diabetes (T2D) and obesity have emerged as major public health crises. These conditions increase the risk of cardiovascular diseases and cause microvascular dysfunction. Patients with T2D also show deficits in wound healing and tissue repair. Although the mechanisms leading to T2D are not well understood, recent work has shown that the states of diabetes and obesity are associated with low-grade chronic inflammation, which triggers and sustains insulin resistance in target tissues. This project is to test the hypothesis that chronic inflammation in obesity and diabetes is sustained in part due to the failure of pro-resolving pathways. This hypothesis predicts that innate immune responses activated in obesity and diabetes fail to resolve leading to chronic inflammation and insulin resistance. It also predicts that restoration of endogenous pro-resolving mediators should extinguish inflammation and restore insulin sensitivity.
The specific aims of this project are to: (1) Define changes in resolution of inflammation during diabetes and obesity;(2) Determine whether restoring resolution will diminish inflammation and insulin resistance;and (3) Identify the mechanism by which promotion of resolution affects insulin resistance. To accomplish these aims we will examine the time course of the development and the resolution of acute inflammation. We will measure changes in pro-resolving lipid mediators by a mass-spectrometry-based lipidomic approach, establish the temporal relationship between changes in lipid mediator synthesis and insulin resistance, and identify the mechanisms by which diabetes and obesity affect the biosynthesis of pro-resolution mediators. To assess the functional significance of the changes in resolution in diabetes and obesity, we will test whether treatment with resolvin D1 (RvD1) will correct the resolution defect and improve glucose tolerance, systemic insulin resistance, and wound healing in high-fat fed and db/db mice. We will determine how RvD1 affects vascular inflammation and adipose-tissue macrophage phenotype. To delineate the mechanism of action, we will examine whether obesity and diabetes affects the expression and function of the RvD1-receptor, Frp2, in macrophages and adipose tissue, and whether Frp2 deletion will abolish the pro-resolving effects of RvD1, as well as its ability to diminish chronic inflammation, insulin resistance, and promote wound healing. To distinguish between the effect of RvD1 on macrophages and adipocytes, and as a gain-of-function test of our hypothesis, we will test whether myeloid- specific overexpression of human FPR2 will enhance resolution of inflammation in diabetes and promote the pro-resolving actions of RvD1. We will identify the mechanisms by which binding of RvD1 to Fpr2 promotes macrophage phagocytosis. Results of this project will provide new knowledge about the processes that sustain chronic adipose tissue inflammation and promote insulin resistance in diabetes and obesity, and could lead to the development of an entirely new approach for the treatment of insulin resistance and wound healing in diabetes and obesity.
This project will provide a new understanding of the mechanisms that contribute to chronic inflammation in diabetes and obesity and will provide new avenues for treating insulin resistance in diabetes and obesity. These results could also be developed as an adjunct treatment for promoting resolution of inflammation and wound healing in diabetics.
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