The role of T cells in adipose tissue inflammation and insulin resistance during weight cycling

T 细胞在体重循环过程中脂肪组织炎症和胰岛素抵抗中的作用

• 批准号: 10347316
• 负责人: Matthew Alexander Cottam
• 金额: $ 1.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347316
• 关键词: Acute; Adaptive Immune System; Address; Adipocytes; Adipose tissue; Affect; Age; Animals; Antigens; Automobile Driving; Behavior; Body Weight decreased; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell Count; Cell Survival; Cells; Characteristics; Clonality; Clone Cells; Control Animal; Development; Diabetes Mellitus; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Gene Expression Profile; Genetic Models; Genetic Transcription; Glucose; Glucose Clamp; Glucose Intolerance; Goals; Gold; Heart; Homeostasis; Human; Immune; Immune system; Impairment; Inflammation; Inflammatory; Insulin Resistance; Link; Literature; Membrane Proteins; Memory; Metabolic; Metabolic Diseases; Metabolism; Modeling; Monoclonal Antibodies; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Obesity; Outcome; Persons; Phenotype; Play; Population; Prevalence; Production; Recovery; Reporting; Resolution; Risk; Role; Societies; Surface; T cell clonality; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; Tissues; Tumor-infiltrating immune cells; Visceral; Weight; Weight Gain; Work; adverse outcome; base; blood glucose regulation; cardiovascular disorder risk; comorbidity; cytokine; design; diet-induced obesity; experience; experimental study; glucose tolerance; glucose uptake; in vivo Model; insight; insulin sensitivity; male; metabolic phenotype; mouse model; novel; obesogenic; programmed cell death protein 1; response; restraint; therapeutic target; weight maintenance

Project Summary On average, people who successfully lose weight will regain 80% of the lost weight within 5 years. Bouts of weight loss (WL) and weight regain, referred to as “weight cycling” (WC), are associated with increased risk of cardiovascular disease and of development of type 2 diabetes mellitus in humans. To identify causes and correlation of the progressive metabolic dysregulation observed in humans who WC, we have developed a mouse model of WC in which alternating 60% high and 10% low-fat diets robustly induce cycles of weight gain and WL. Glucose tolerance in WC animals is impaired compared to age, weight, and adiposity-matched high-fat fed control animals. Alterations in systemic glucose regulation is partially dependent on adaptive immune cells that infiltrate metabolic tissues, including adipose tissue (AT), during progression of obesity. However, the phenotype of these important cells during WL and WC has not been characterized. Premised on novel preliminary findings that CD8+ T cells display markers of immunotolerance during WL and aggressive inflammatory potential during WC, I hypothesize that AT CD8+ T cells transiently become tolerant during WL, but are potently reactivated after WC and are necessary for impaired insulin sensitivity observed during WC. We have observed a loss of T cell receptor diversity in visceral AT during obesity, indicating that T cells clonally expand in response to a nutritionally-triggered antigen. To further elucidate the role that clonal T cell expansion may play in systemic glucose handling in WL and WC mice, I will characterize T cells with single-cell resolution using sequencing and flow cytometry-based approaches. Additionally, we will use depletion and genetic models to block long-lived CD8+ T cells from contributing to glucose intolerance observed during WC. Obesity-experienced CD8+ T cells will be depleted using monoclonal antibodies prior to WL. After recovery, animals will again be challenged with diet-induced obesity to identify if inexperienced CD8+ T cells are unable to promote insulin resistance characteristic of AT after WC. Concomitantly, CD70-/- mice, which fail to maintain survival of activated T cells long-term, will be WC and metabolically phenotyped to determine whether it is long-lived AT-resident CD8+ T cells that are necessary for driving systemic glucose dysregulation. Both of these models will be phenotyped with gold-standard hyperinsulinemic euglycemic clamps to expose differences in insulin sensitivity from control mice. Ultimately, this proposal seeks to fill an unmet need in the metabolism and inflammation fields regarding T cell phenotype and function during AT remodeling. As a result, the outcomes of this project will influence subsequent work by providing clear insight into mechanisms of T-cell driven inflammation and therapeutic targets for weight maintenance.

项目摘要 平均而言，成功减肥的人将在5年内持续减肥的80％。 体重减轻（WL）和体重仍然存在，称为“体重骑自行车”（WC），与 人类心血管疾病的风险增加和2型糖尿病的发展。到 确定在人类中观察到的进行性代谢失调的原因和相关性 WC，我们已经开发了WC的小鼠模型，其中替代品高60％和10％的低脂饮食 坚固地诱导体重增加和WL的周期。比较WC动物中的葡萄糖耐受性受损 年龄，体重和肥胖匹配的高脂喂养动物。全身葡萄糖的改变 调节部分取决于浸润代谢组织的适应性免疫细胞，包括 肥胖进展过程中脂肪组织（AT）。但是，这些重要细胞的表型 在WL和WC期间尚未表征。以CD8+ T的新初步发现为前提 细胞在WL期间显示不亮的标志物，在WC期间显示出攻击性的炎症潜力， 我假设在CD8+ T细胞在WL期间瞬时变得耐受性，但可能是 WC后重新激活，对于在WC期间观察到的胰岛素敏感性受损是必需的。我们 观察到肥胖症期间内脏中T细胞受体多样性的丧失，表明T细胞 响应于营养触发的抗原，克隆扩展。进一步阐明克隆的作用 T细胞扩展可能在WL和WC小鼠中的全身葡萄糖处理中发挥作用，我将表征T细胞 使用基于测序和基于流式细胞仪的方法进行单细胞分辨率。此外，我们会的 使用部署和遗传模型阻止长寿命的CD8+ T细胞不从葡萄糖贡献 在WC期间观察到的intlerance。肥胖经验的CD8+ T细胞将使用单克隆 WL之前的抗体。恢复后，动物将再次受到饮食引起的肥胖症的挑战 确定缺乏经验的CD8+ T细胞无法促进以后的胰岛素抵抗特征 厕所。同时，无法长期保持活化T细胞存活的CD70 - / - 小鼠将是 WC和代谢表型，以确定它是否是长期寿命的CD8+ T细胞 对于驱动全身葡萄糖失调所必需。这两个模型都将与 金色标准的高胰岛素纤维血糖夹，暴露于胰岛素敏感性的差异 控制小鼠。最终，该提议试图满足新陈代谢和注射的未满足需求 有关在重塑时进行T细胞表型和功能的领域。结果，结果的结果 项目将通过对T细胞驱动器的机制清晰洞悉，影响后续工作 维持体重的炎症和治疗靶标。