Mechanisms of T cell inflammation in obesity-induced type 2 diabetes

肥胖引起的 2 型糖尿病中 T 细胞炎症的机制

• 批准号: 9130822
• 负责人: Nancie MacIver
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-21 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130822
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Animals; Body Weight; Cell Count; Cell Differentiation process; Cell physiology; Cells; Cellular Metabolic Process; Data; Development; Diabetes Mellitus; Eating; Effector Cell; Energy Metabolism; Epidemic; Equilibrium; FRAP1 gene; Glucose Transporter; Health; High Fat Diet; Hormones; Immune; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knockout Mice; Leptin; Link; Lipids; Lymphocyte; Lymphoid; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Play; Population; Process; Production; Proteins; Regulatory T-Lymphocyte; Reporting; Resistance development; Risk; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; T cell differentiation; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Visceral; Weight; cytokine; glucose metabolism; glucose uptake; hypoxia inducible factor 1; insight; knockout animal; leptin receptor; macrophage; meetings; metabolic profile; new therapeutic target; novel; novel marker; novel therapeutic intervention; oxidation; prevent; programs; response

 DESCRIPTION (provided by applicant): Obesity predisposes to both systemic and adipose-tissue inflammation that is associated with the development of metabolic syndrome, including insulin resistance leading to type 2 diabetes. In obese adipose tissue, there is an influx of immune cells, particularly macrophages and lymphocytes, which secrete inflammatory cytokines that promote this phenotype. T lymphocytes (T cells) have an early and critical role in obesity-induced inflammation, as adipose-resident T cells in obesity are activated and undergo a shift in subset differentiation, leading to increased inflammatory effector T cells (Teff) and decreased suppressive regulatory T cells (Treg), which precedes the recruitment of macrophages into adipose tissue. Understanding how T cells are differentiated and activated in obesity is a critically important step in understanding the mechanism of obesity-driven inflammation. Activation of T cells results in an increased metabolic demand to fuel T cell proliferation and cytokine production. Inflammatory Teff cells meet this increased metabolic demand by upregulating glucose uptake and metabolism, whereas Treg cells utilize a distinct metabolic program of lipid oxidation. These metabolic programs are essential for each subset; therefore, identification of factors that promote glucose metabolism may alter the Teff/Treg balance and mediate obesity-associated inflammation. We have identified a novel link between nutritional status and T cell activation and metabolism through the adipokine leptin. Leptin is secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin is well-known for its ability to regulate food intake and whole body metabolism, but it is also a pro- inflammatory cytokine, with important effects on immune cell number and function. We have now shown that leptin promotes T cell glucose metabolism to fuel Teff activation. Therefore, while T cell activation in obesity is likely altered via multiple mechanisms, increased circulating leptin may be a key factor. The objective of this proposal is to identify mechanisms by which obesity alters the Teff/Treg balance, resulting in inflammation and subsequent insulin resistance leading to type 2 diabetes. We hypothesize that obesity-associated hyperleptinemia directly promotes T cell glycolytic metabolism to drive T cell inflammation. To test our hypothesis we propose the following Specific Aims: (1) Identify the role of leptin in Teff versus Treg differentiation and metabolism and in the development of insulin resistance in obesity. (2) Examine signaling pathways by which leptin may mediate changes to T cell differentiation and metabolism to promote inflammation and insulin resistance in obesity. At the completion of this project, we will better understand the role of leptin in linking nutritional status with immune cell metabolism and differentiation in obesity. Understanding mechanisms by which T cells respond to obesity may identify novel markers and targets for the treatment of diabetes and metabolic disease.

 描述（由申请人提供）：肥胖易患全身性和脂肪组织炎症，这与代谢综合征的发展有关，包括导致2型糖尿病的胰岛素抵抗。在肥胖脂肪组织中，存在免疫细胞的流入，特别是巨噬细胞和淋巴细胞，其分泌促进该表型的炎性细胞因子。T淋巴细胞（T细胞）在肥胖诱导的炎症中具有早期和关键作用，因为肥胖中的脂肪驻留T细胞被激活并经历亚群分化的转变，导致炎性效应T细胞（Teff）增加和抑制性调节T细胞（Treg）减少，这先于巨噬细胞募集到脂肪组织中。了解T细胞如何在肥胖中分化和激活是了解肥胖驱动的炎症机制的关键一步。T细胞的活化导致对燃料T细胞增殖和细胞因子产生的代谢需求增加。炎性Teff细胞通过上调葡萄糖摄取和代谢来满足这种增加的代谢需求，而Treg细胞利用脂质氧化的独特代谢程序。这些代谢程序对每个亚群都是必不可少的;因此，鉴定促进葡萄糖代谢的因子可能会改变Teff/Treg平衡并介导肥胖相关炎症。我们已经确定了一个新的联系营养状况和T细胞的活化和代谢，通过脂肪因子瘦素。瘦素的分泌与脂肪细胞的质量成比例，因此在肥胖症中增加。众所周知，瘦素具有调节食物摄入和全身代谢的能力，但它也是一种促炎细胞因子，对免疫细胞数量和功能具有重要影响。我们现在已经表明，瘦素促进T细胞葡萄糖代谢，以燃料Teff激活。因此，虽然肥胖症中的T细胞活化可能通过多种机制改变，但循环瘦素增加可能是一个关键因素。该提案的目的是确定肥胖改变Teff/Treg平衡的机制，导致炎症和随后的胰岛素抵抗，导致2型糖尿病。我们假设肥胖相关的高瘦素血症直接促进T细胞糖酵解代谢，从而驱动T细胞炎症。为了验证我们的假设，我们提出了以下具体目的：（1）确定瘦素在Teff与Treg分化和代谢中的作用，以及在肥胖症中胰岛素抵抗的发展中的作用。(2)检查瘦素可能介导T细胞分化和代谢变化的信号通路，以促进肥胖症中的炎症和胰岛素抵抗。在这个项目完成后，我们将更好地了解瘦素在肥胖中将营养状况与免疫细胞代谢和分化联系起来的作用。了解T细胞对肥胖的反应机制可能会发现治疗糖尿病和代谢疾病的新标志物和靶点。