Role of the Interleukin12/STAT4 Pathway in Insulin Resistance and Atherosclerosis

Interleukin12/STAT4 通路在胰岛素抵抗和动脉粥样硬化中的作用

• 批准号: 8587826
• 负责人: JERRY L. NADLER
• 金额: $ 4.4万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8587826
• 关键词: Address; Adipocytes; Adipose tissue; Adoptive Cell Transfers; Adoptive Transfer; Affect; Aorta; Atherosclerosis; Blood Vessels; Body Weight; Bone Marrow Transplantation; Cardiovascular Diseases; Cells; Central obesity; Cholesterol; Development; Diabetes Mellitus; Diet; Eating; Equilibrium; Family; Fatty acid glycerol esters; Flow Cytometry; Gene Expression; Genes; Glucose tolerance test; Hematopoietic; Homing; Immune; Immune Cell Activation; Immune response; Immunohistochemistry; In Vitro; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Insulin Signaling Pathway; Interleukin-12; Label; Lead; Leukocytes; Link; Lisofylline; Measures; Metabolic; Metabolic syndrome; Modeling; Mus; Myocardial Infarction; Natural Killer Cells; Obesity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Production; Rag1 Mouse; Regulation; Research; Risk; Risk Factors; Role; STAT4 protein; Signal Transduction; Specificity; T-Lymphocyte; Testing; Visceral; adipocyte differentiation; atherogenesis; cell mediated immune response; cell motility; chemokine; cytokine; feeding; gene induction; glucose uptake; improved; in vivo; inhibitor/antagonist; innovation; insulin sensitivity; insulin signaling; insulin tolerance; macrophage; migration; monocyte; prevent; response; therapeutic target

DESCRIPTION (provided by applicant): Evidence suggests an important link between immune cell activation and insulin resistance (IR) in states associated with increases in visceral adipose tissue (AT). The interleukin-12 (IL-12) family of cytokines is particularly relevant given their importance in cell-mediated immune responses and downstream inflammatory gene induction. IL-12 has been shown to be directly involved in the progression of atherosclerosis. Signal transducer and activator of transcription 4 (STAT4), which is activated by IL-12, induces the expression of several major genes linked to inflammation in atherosclerosis and the metabolic syndrome. The central hypothesis is that IL-12/Stat-4 pathway plays a critical role in the induction of IR in visceral and peri-aortic adipose tissue and this will affect the immune response in aortas and further accelerate atherosclerosis. Aims to address this include: Aim 1. Determine mechanisms related to IL-12/STAT4 deficiency in hematopoetic and non-hematopoetic cells on protection against obesity induced insulin resistance, and adipose tissue inflammation. Our hypothesis is that STAT4 deficiency prevents IR in diet-induced obesity by changes in T cell abundance and phenotype and macrophage polarization in adipose tissue and by reducing inflammation and improving insulin sensitivity in visceral adipocytes. Aim 1.1: Determine the in vivo effect of IL-12 or STAT4 deficiency in the hematopoietic (T cells, NK cells) vs. non-hematopoetic compartment (adipocyte) for the development of IR and obesity. Aim 1.2: Determine role of IL-12/STAT4 deficiency on in vivo and in vitro T cell migration in adipose tissue, T cell and macrophage phenotype and polarization and production of pro-inflammatory cytokines. Aim 1.3: Mechanistically investigate functional roles of IL-12/STAT4 deficiency in adipocytes on glucose uptake and insulin signaling in response to high fat diet and cytokine stimulation. Aim 2. Determine effects of IL-12/Stat-4 pathway inhibition on AT inflammation-associated atherosclerosis. What is the specific role of peri-aortic and visceral AT in adipose tissue-related atherosclerosis? Aim 2.1: Examine effects of Stat-4 deficiency on atherosclerosis with and without AT inflammation in Stat -4-/- Ldlr-/- mice fed a diabetogenic diet (DD) to induce IR and DD with additional cholesterol (DDC) to induce atherosclerosis and AT inflammation. Aim 2.2: Test the effects of AT inflammation, Stat-4 deficiency on leukocyte recruitment into peri-aortic, visceral AT and aortas. Aim 2.3: Determine the involvement of AT inflammation, Stat-4 deficiency and the conditions of AT inflammation-related atherogenesis on local immune response in peri-aortic, visceral AT and aortas. Aim 2.4: Investigate effects and specificity of IL-12 inhibition on Stat-4+/+ and Stat-4 deficient model of AT- inflammation accelerated atherosclerosis in mice fed DDC diet. The completed project should identify an innovative therapeutic target that could lead to new treatment to reduce atherosclerosis associated with central obesity insulin resistance and diabetes.

描述（由申请人提供）：证据表明，在内脏脂肪组织（AT）增加相关的状态下，免疫细胞激活和胰岛素抵抗（IR）之间存在重要联系。鉴于白细胞介素 12 (IL-12) 细胞因子家族在细胞介导的免疫反应和下游炎症基因诱导中的重要性，它们尤其重要。 IL-12已被证明直接参与动脉粥样硬化的进展。信号转导器和转录激活剂 4 (STAT4) 由 IL-12 激活，诱导与动脉粥样硬化和代谢综合征中的炎症相关的几个主要基因的表达。中心假设是IL-12/Stat-4通路在内脏和主动脉周围脂肪组织中IR的诱导中发挥关键作用，这将影响主动脉的免疫反应并进一步加速动脉粥样硬化。解决这一问题的目的包括： 目标 1. 确定与造血和非造血细胞中 IL-12/STAT4 缺乏相关的机制，以防止肥胖引起的胰岛素抵抗和脂肪组织炎症。我们的假设是，STAT4 缺陷通过改变脂肪组织中的 T 细胞丰度和表型以及巨噬细胞极化，以及通过减少炎症和改善内脏脂肪细胞的胰岛素敏感性来预防饮食诱导的肥胖中的 IR。目标 1.1：确定造血细胞（T 细胞、NK 细胞）与非造血细胞（脂肪细胞）中 IL-12 或 STAT4 缺乏对 IR 和肥胖发展的体内影响。目标 1.2：确定 IL-12/STAT4 缺陷对体内和体外脂肪组织中 T 细胞迁移、T 细胞和巨噬细胞表型以及促炎细胞因子的极化和产生的作用。目标 1.3：从机制上研究脂肪细胞中 IL-12/STAT4 缺乏对响应高脂肪饮食和细胞因子刺激的葡萄糖摄取和胰岛素信号传导的功能作用。目标 2. 确定 IL-12/Stat-4 通路抑制对 AT 炎症相关动脉粥样硬化的影响。主动脉周围和内脏 AT 在脂肪组织相关动脉粥样硬化中的具体作用是什么？目标 2.1：在喂食致糖尿病饮食 (DD) 的 Stat -4-/- Ldlr-/- 小鼠中检查 Stat-4 缺陷对有或没有 AT 炎症的动脉粥样硬化的影响，以诱导 IR 和 DD 并添加额外的胆固醇 (DDC) 以诱导动脉粥样硬化和 AT 炎症。目标 2.2：测试 AT 炎症、Stat-4 缺乏对主动脉周围、内脏 AT 和主动脉白细胞募集的影响。目标 2.3：确定 AT 炎症、Stat-4 缺乏以及 AT 炎症相关动脉粥样硬化形成条件对主动脉周围、内脏 AT 和主动脉局部免疫反应的影响。目标 2.4：研究 IL-12 抑制对 Stat-4+/+ 和 Stat-4 缺陷模型 AT-炎症加速动脉粥样硬化的影响和特异性。已完成的项目应确定一个创新的治疗目标，该目标可能导致新的治疗方法，以减少与中心性肥胖胰岛素抵抗和糖尿病相关的动脉粥样硬化。