Resolution of inflammation in obesity and diabetes: Role of lipid mediators

描述（由申请人提供）：2型糖尿病（T2 D）和肥胖已成为主要的公共卫生危机。这些情况增加了心血管疾病的风险，并导致微血管功能障碍。患有T2 D的患者还显示出伤口愈合和组织修复的缺陷。虽然导致T2 D的机制尚未得到很好的理解，但最近的研究表明，糖尿病和肥胖症的状态与低度慢性炎症有关，后者触发并维持靶组织中的胰岛素抵抗。这个项目是为了验证一个假设，即肥胖和糖尿病的慢性炎症部分是由于前解决途径的失败而持续的。这一假说预测，肥胖和糖尿病中激活的先天免疫反应未能解决，导致慢性炎症和胰岛素抵抗。它还预测，内源性促消退介质的恢复应该会消除炎症并恢复胰岛素敏感性。该项目的具体目标是：（1）定义糖尿病和肥胖症期间炎症消退的变化;（2）确定恢复消退是否会减少炎症和胰岛素抵抗;（3）确定促进消退影响胰岛素抵抗的机制。为了实现这些目标，我们将研究急性炎症的发展和解决的时间过程。我们将通过基于质谱的脂质组学方法测量促消退脂质介质的变化，建立脂质介质合成变化与胰岛素抵抗之间的时间关系，并确定糖尿病和肥胖影响促消退介质生物合成的机制。为了评估糖尿病和肥胖症消退变化的功能意义，我们将测试用消退素D1（RvD 1）治疗是否会纠正高脂喂养和db/db小鼠的消退缺陷并改善葡萄糖耐量、全身胰岛素抵抗和伤口愈合。我们将确定RvD 1如何影响血管炎症和脂肪组织巨噬细胞表型。为了阐明作用机制，我们将研究肥胖和糖尿病是否影响RvD 1受体Frp 2在巨噬细胞和脂肪组织中的表达和功能，以及Frp 2缺失是否会消除RvD 1的促消退作用，以及其减少慢性炎症、胰岛素抵抗和促进伤口愈合的能力。为了区分RvD 1对巨噬细胞和脂肪细胞的作用，并作为我们假设的功能获得性测试，我们将测试人FPR 2的骨髓特异性过表达是否会增强糖尿病炎症的消退并促进RvD 1的促消退作用。我们将确定RvD 1与Fpr 2结合促进巨噬细胞吞噬作用的机制。该项目的结果将提供有关维持慢性脂肪组织炎症和促进糖尿病和肥胖症胰岛素抵抗的过程的新知识，并可能导致开发一种全新的方法来治疗糖尿病和肥胖症的胰岛素抵抗和伤口愈合。

DESCRIPTION (provided by applicant): 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.