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

肥胖和糖尿病炎症的解决：脂质介质的作用

• 批准号: 8885982
• 负责人: Matthew R Spite
• 金额: $ 36.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885982
• 关键词: Acute; Adipocytes; Adipose tissue; Affect; Anabolism; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Binding; Cells; Chronic; Defect; Development; Diabetes Mellitus; Diet; Disease; Dopamine D1 Receptor; Excision; Failure; Fatty acid glycerol esters; Health; Homeostasis; Human; Immune; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Injury; Insulin; Insulin Resistance; Interruption; Invaded; Kidney Diseases; Knowledge; Lead; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Metabolic; Microvascular Dysfunction; Mus; Myelogenous; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Phagocytes; Phagocytosis; Phenotype; Process; Public Health; Recurrence; Resolution; Retinal Diseases; Risk; Role; Signal Transduction; Stimulus; Testing; Therapeutic; Time; Tissue Expansion; Tissues; Work; Wound Healing; base; cardiovascular disorder risk; db/db mouse; diabetic; feeding; gain of function; glucose tolerance; improved; insulin sensitivity; lipid mediator; macrophage; mouse model; novel strategies; novel therapeutic intervention; overexpression; pathogen; prevent; programs; response; restoration; tissue repair; vascular inflammation

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.

描述（由申请人提供）：2型糖尿病（T2D）和肥胖已成为重大的公共卫生危机。这些情况会增加患心血管疾病的风险，并导致微血管功能障碍。T2D患者也表现出伤口愈合和组织修复的缺陷。虽然导致T2D的机制尚不清楚，但最近的研究表明，糖尿病和肥胖状态与低度慢性炎症有关，后者在靶组织中触发并维持胰岛素抵抗。这个项目是为了验证肥胖和糖尿病的慢性炎症是部分由于促分解途径的失败而持续的假设。这一假说预测，肥胖和糖尿病激活的先天免疫反应无法解决，导致慢性炎症和胰岛素抵抗。它还预测内源性促溶解介质的恢复应该可以消除炎症并恢复胰岛素敏感性。该项目的具体目的是：(1)确定糖尿病和肥胖症期间炎症消退的变化；(2)确定恢复分辨率是否会减少炎症和胰岛素抵抗；(3)确定促进解决影响胰岛素抵抗的机制。为了达到这些目的，我们将研究急性炎症的发展和解决的时间进程。我们将通过基于质谱的脂质组学方法测量促溶解介质的变化，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溶解介质生物合成的机制。为了评估分辨力变化在糖尿病和肥胖症中的功能意义，我们将测试分辨力蛋白D1 （RvD1）治疗是否会纠正分辨力缺陷，改善高脂肪喂养和db/db小鼠的葡萄糖耐量、全身胰岛素抵抗和伤口愈合。我们将确定RvD1如何影响血管炎症和脂肪组织巨噬细胞表型。为了描述其作用机制，我们将研究肥胖和糖尿病是否会影响巨噬细胞和脂肪组织中RvD1受体Frp2的表达和功能，以及Frp2缺失是否会取消RvD1的促溶解作用，以及RvD1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RvD1对巨噬细胞和脂肪细胞的影响，并作为我们假设的功能获得性检验，我们将测试人类FPR2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RvD1的促消退作用。我们将确定RvD1与Fpr2结合促进巨噬细胞吞噬的机制。该项目的结果将为糖尿病和肥胖症中维持慢性脂肪组织炎症和促进胰岛素抵抗的过程提供新的知识，并可能导致糖尿病和肥胖症中胰岛素抵抗和伤口愈合的全新治疗方法的发展。