Immunologic memory to metabolic cycling

代谢循环的免疫记忆

• 批准号: 10045934
• 负责人: Alyssa H Hasty
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045934
• 关键词: Adipocytes; Adipose tissue; Antibodies; Antigens; Biological Assay; Body Weight; Body Weight decreased; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell Count; Cells; Clonal Expansion; Data; Defect; Development; Disease; Epidemic; Equilibrium; Fat-Restricted Diet; Fatty acid glycerol esters; Flow Cytometry; General Population; Genes; Human; Immune; Immune response; Immune system; Immunologic Memory; Impairment; Incidence; Inflammation; Inflammatory; Insulin Resistance; Kinetics; Lead; Light; Liver; Lymphocyte Count; Memory; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathologic; Phase; Phenotype; Play; Population; Prevalence; Publishing; Regulatory T-Lymphocyte; Risk; Scientist; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Weight; Weight Gain; adaptive immune response; adaptive immunity; comorbidity; diabetes risk; effector T cell; fasting glucose; feeding; glucose tolerance; insulin sensitivity; insulin signaling; macrophage; metabolic phenotype; mouse model; obesity development; prevent; response; Adipocytes; Adipose tissue; Antibodies; Antigens; Biological Assay; Body Weight; Body Weight decreased; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cell Count; Cells; Clonal Expansion; Data; Defect; Development; Disease; Epidemic; Equilibrium; Fat-Restricted Diet; Fatty acid glycerol esters; Flow Cytometry; General Population; Genes; Human; Immune; Immune response; Immune system; Immunologic Memory; Impairment; Incidence; Inflammation; Inflammatory; Insulin Resistance; Kinetics; Lead; Light; Liver; Lymphocyte Count; Memory; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathologic; Phase; Phenotype; Play; Population; Prevalence; Publishing; Regulatory T-Lymphocyte; Risk; Scientist; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Weight; Weight Gain; adaptive immune response; adaptive immunity; comorbidity; diabetes risk; effector T cell; fasting glucose; feeding; glucose tolerance; insulin sensitivity; insulin signaling; macrophage; metabolic phenotype; mouse model; obesity development; prevent; response

The prevalence of obesity and associated co-morbidities, including type 2 diabetes and cardiovascular disease (CVD), has increased dramatically in the past several decades. While weight loss is the ideal approach to reduce the negative metabolic consequences of obesity, it is clear that sustained weight loss is difficult to achieve. In fact, only 20% of people who lose at least 10% of their body weight are able to maintain that loss for greater than 2 years. These bouts of weight loss followed by subsequent weight gain lead to “weight-cycling”. Interestingly, several studies in humans demonstrate that weight-cycling increases the risk of developing metabolic diseases. While the potentially deleterious effects of weight-cycling are recognized, the mechanisms by which weight- cycling increases metabolic dysfunction remain unknown. During the past decade, we have come to understand that the immune system plays a key role in the pathological consequences of obesity. Metabolic organs such as the liver, muscle, and adipose tissue (AT) accumulate immune cells that subsequently impact the insulin sensitivity of the parenchymal cells. In particular, obesity results in a dramatic increase in the number of inflammatory AT macrophages and AT T lymphocytes (ATTs). Interestingly, the accumulation of T cells in obese AT appears to be antigen-driven and is also characterized by the formation of memory cells. To determine if weight cycling alters immune responses in AT, we developed a mouse model of weight cycling using alternating high fat (HF) and low fat (LF) diet feeding. Similar to what is seen in humans; the weight-cycled mice had increased fasting glucose levels and impaired systemic glucose tolerance compared to mice that gained weight but did not cycle (weight-gain controls). Furthermore, AT-specific insulin signaling was abolished in the weight-cycled mice. At the end of the study, the macrophage populations in AT were unchanged in their number and phenotype. However, ATT number and the expression of multiple TH1-associated genes were significantly increased in the AT of the weight-cycled mice. These data demonstrate that weight cycling induces a potent T cell-driven adaptive immune response in the AT and suggest that weight cycling actually induce a secondary adaptive immune response. Thus, the overall hypothesis of this application is: weight-cycling results in an accelerated secondary adaptive immune response that heightens inflammation in AT, leading to local and systemic insulin resistance. This hypothesis will be tested in the following 3 aims: 1) To determine whether weight cycling alters ATT phenotype and function; 2) To determine if weight cycling induces secondary immune responses in AT; 3) To determine whether weight cycling modulates regulatory T cell (Treg) phenotype and function.

肥胖和相关的合并症的患病率，包括2型糖尿病和 在过去的几十年中，心血管疾病（CVD）急剧增加。而重量 损失是减少肥胖症负面代谢后果的理想方法，很明显 持续的体重减轻很难实现。实际上，只有20％的人损失了至少10％的人 体重能够维持超过2年的损失。这些体重减轻 然后随后的体重增加导致“体重循环”。有趣的是，在人类中进行了一些研究 证明重量循环会增加患有代谢疾病的风险。而 重量循环的潜在删除效应是确认的，重量的机制 循环增加代谢功能障碍仍然未知。在过去的十年中，我们来了 了解免疫系统在肥胖的病理后果中起关键作用。 肝脏，肌肉和脂肪组织（AT）等新陈代谢器官会积累免疫细胞 随后影响副群细胞的胰岛素敏感性。特别是，肥胖会导致 巨噬细胞和T淋巴细胞处炎症的数量急剧增加（ATTS）。 有趣的是，T细胞在肥胖处的积累似乎是抗原驱动的，也是 以记忆细胞的形成为特征。确定体重循环是否改变免疫 AT的响应，我们使用替代高脂（HF）和 低脂（LF）饮食喂养。类似于人类所见；体重偶尔小鼠增加了 与增加体重的小鼠相比 但没有循环（体重增加控制）。此外，在 重量循环的小鼠。在研究结束时，AT中的巨噬细胞种群不变 在它们的数量和表型中。但是，ATT编号和多个Th1相关的表达 体重偶有小鼠的AT中的基因显着增加。这些数据表明 重量循环诱导AT中潜在的T细胞驱动的适应性免疫反应，并表明 重量循环实际上会引起次级自适应免疫响应。那，总体假设 此应用的是：重量循环导致加速的次级自适应免疫 反应增强了AT的注射，导致局部和全身胰岛素抵抗。 该假设将在以下3个目标中进行检验：1）确定重量循环是否改变 ATT表型和功能； 2）确定重量循环是否诱导次级免疫回报 在at; 3）确定重量循环是否调节调节性T细胞（TREG）表型和 功能。