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）：肥胖容易发生全身性和脂肪组织炎症，这与代谢综合征的发生有关，包括导致 2 型糖尿病的胰岛素抵抗。在肥胖的脂肪组织中，免疫细胞大量涌入，尤其是免疫细胞。巨噬细胞和淋巴细胞会分泌促进这种表型的炎症细胞因子，T 淋巴细胞（T 细胞）作为肥胖中的脂肪驻留 T 细胞，在肥胖引起的炎症中发挥着早期且关键的作用。被激活并经历分化子集的转变，导致炎症效应 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 细胞在肥胖中如何分化和激活。这是理解肥胖引起的炎症机制的一个至关重要的步骤，T细胞的激活导致代谢需求增加，以促进T细胞增殖和细胞因子的产生，而炎症Teff细胞通过上调葡萄糖的摄取和产生来满足这种增加的代谢需求。代谢，而 Treg 细胞利用不同的脂质氧化代谢程序，因此，识别促进葡萄糖代谢的因素可能会改变 Teff/Treg 平衡并介导肥胖相关炎症。营养状况与 T 细胞活化和代谢之间的新联系是通过脂肪细胞因子瘦素按比例分泌的，因此瘦素因其调节食物摄入和全身代谢的能力而增加。它也是一种促炎细胞因子，对免疫细胞的数量和功能具有重要影响，我们现在已经证明，瘦素可以促进 T 细胞葡萄糖代谢，从而促进 Teff 激活，因此，虽然肥胖中的 T 细胞激活可能会通过多种机制发生改变。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、导致炎症和随后导致 2 型糖尿病的胰岛素抵抗的机制。 T细胞为了检验我们的假设，我们提出以下具体目标：(1) 确定瘦素在 Teff 与 Treg 分化和代谢以及肥胖中胰岛素抵抗发展中的作用。瘦素可能介导 T 细胞分化和代谢的变化，从而促进肥胖中的炎症和胰岛素抵抗。该项目完成后，我们将更好地了解瘦素在将营养状况与肥胖中的免疫细胞代谢和分化联系起来方面的作用。机制由对肥胖做出反应的 T 细胞可能会识别出治疗糖尿病和代谢疾病的新标记物和靶点。