T Cells, Macrophages, Chemokines, and Adiposopathy in Diet-Induced Obesity

饮食引起的肥胖中的 T 细胞、巨噬细胞、趋化因子和脂肪病

• 批准号: 7825438
• 负责人: CHRISTIE Mitchell BALLANTYNE
• 金额: $ 35.75万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-05 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825438
• 关键词: Acids; Adipocytes; Adipose tissue; Adult; CCL2 gene; CCR5 gene; Cardiovascular Diseases; Cells; Chemokine (C-C Motif) Receptor 5; Child; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease; Epidemic; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Grant; Hepatic; Human; ITGAM gene; ITGAX gene; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Laboratories; Lead; Leukocytes; Liver; Macrophage Activation; Maintenance; Metabolic; Metabolism; Monocyte Chemoattractant Protein-1; Mus; Obese Mice; Obesity; Palmitic Acids; Pathway interactions; Process; Production; RANTES; Recruitment Activity; Resistance development; Risk; Role; Saturated Fatty Acids; T-Lymphocyte; T-Lymphocyte Subsets; TLR2 gene; TLR4 gene; Testing; Toll-Like Receptor 2; Triglycerides; Visceral; adipocyte differentiation; chemokine; cytokine; diabetes risk; macrophage; migration; monocyte; monocyte chemoattractant protein 1 receptor; mouse model; novel; public health relevance; response

DESCRIPTION (provided by applicant): Obesity increases the risk for developing both diabetes and cardiovascular disease (CVD). Increased adipose tissue inflammation, with increased chemokine and cytokine expression and macrophage accumulation, contributes to adipose tissue dysfunction, insulin resistance, and development of both diabetes and CVD. Using a mouse model of obesity induced by a high-fat (HF) diet rich in saturated fatty acids (SFAs), we made the novel finding that T cells are increased and the chemokine regulated on activation, normal T-cell expressed and secreted (RANTES) and its receptor, CCR5, along with monocyte chemoattractant protein-1 (MCP-1) and receptor CCR2, are upregulated in adipose tissue of obese insulin-resistant mice and in human visceral adipose tissue. Both ?? T cells and ?? T cells are resident in adipose tissue of lean mice. Compared with lean mice, obese mice have a significant increase in ?? T cells but not in ?? T cells in adipose tissue. RANTES and MCP-1 increase in adipose tissue early in the development of adiposity induced by the high-SFA diet. Palmitic acid, a long-chain SFA present in high concentration in the HF diet, increases MCP-1 and RANTES expression in adipocytes in vitro. RANTES and MCP-1 secreted by mouse adipose tissue induce T cell and macrophage migration. Deficiency of ?? T cells in mice decreases adipose tissue inflammation induced by the HF diet. Activated T cells inhibit preadipocyte-to-adipocyte differentiation, with significant reduction of triglyceride accumulation in adipocytes, and also induce adipocyte inflammation. The effects of inflammation on adipose tissue function, such as altered FA metabolism with decreased FA deposition and increased FA release by adipocytes, may increase free FA flux to the liver, cause ectopic fat deposition and increased hepatic and systemic inflammation, and increase the risk for diabetes and CVD. We hypothesize that in the development of adiposity induced by a HF diet, dietary SFAs activate adipose resident cells (adipocytes/preadipocytes, T cells, and macrophages) to produce chemokines that recruit and activate T cells, and that T cells are critical to the progression of inflammatory changes in adipose tissue including recruitment and activation of macrophages. These recruited and activated leukocytes cause pathological adipose tissue dysfunctions (adiposopathy), leading to metabolic abnormalities. To test our hypotheses, we propose the following studies: 1. Determine the direct influence of various fatty acids on chemokine production by resident adipose tissue cells including adipocytes, T cells, and macrophages and determine if this influence results from activation through TLR2 and/or TLR4. 2. Determine the contribution of two prominent chemokine pathways (MCP-1/CCR2 and RANTES/CCR5) to T cell/macrophage recruitment and activation in adipose tissue, and determine the contributions of T cells to the inflammatory process in adipose tissue of mice on a HF diet rich in SFAs. 3. Determine mechanisms by which adipose tissue ?? T cells and/or ?? T cells directly alter preadipocyte or adipocyte functions. PUBLIC HEALTH RELEVANCE: Obesity is becoming a global epidemic in both adults and children and increases the risk for developing both diabetes and cardiovascular disease (CVD). CVD has been shown to be an inflammatory disease, and we hypothesize that obesity caused by a high- calorie, high-fat diet increases the body's inflammatory response. To test our hypothesis, we will study the effects of diet-induced obesity on a number of factors related to inflammation in mice and also in human fat cells.

描述（由申请人提供）：肥胖增加患糖尿病和心血管疾病（CVD）的风险。脂肪组织炎症的增加，随着趋化因子和细胞因子表达的增加以及巨噬细胞的积累，有助于脂肪组织功能障碍、胰岛素抵抗以及糖尿病和心血管疾病的发展。利用富含饱和脂肪酸（SFAs）的高脂肪饮食诱导的肥胖小鼠模型，我们发现在肥胖胰岛素抵抗小鼠的脂肪组织和人类内脏脂肪组织中，T细胞增加，正常T细胞表达和分泌（RANTES）及其受体CCR5、单核细胞趋化蛋白-1 （MCP-1）和受体CCR2的激活受到调节。都? ?T细胞和？？T细胞驻留在瘦小鼠的脂肪组织中。与瘦小鼠相比，肥胖小鼠的？？T细胞而不是T细胞？脂肪组织中的T细胞。在高sfa饮食诱导的肥胖发展早期，脂肪组织中的RANTES和MCP-1增加。棕榈酸是一种长链SFA，高浓度存在于HF日粮中，可增加体外脂肪细胞中MCP-1和RANTES的表达。小鼠脂肪组织分泌的RANTES和MCP-1诱导T细胞和巨噬细胞迁移。缺乏？？小鼠体内的T细胞减少HF饮食引起的脂肪组织炎症。激活的T细胞抑制前脂肪细胞向脂肪细胞的分化，显著减少脂肪细胞中甘油三酯的积累，并诱导脂肪细胞炎症。炎症对脂肪组织功能的影响，如改变FA代谢，减少FA沉积，增加脂肪细胞释放FA，可能增加游离FA到肝脏的通量，引起异位脂肪沉积，增加肝脏和全身炎症，增加糖尿病和心血管疾病的风险。我们假设，在HF饮食诱导的肥胖发展过程中，膳食SFAs激活脂肪驻留细胞（脂肪细胞/脂肪前细胞、T细胞和巨噬细胞）产生募集和激活T细胞的趋化因子，而T细胞对脂肪组织炎症变化的进展至关重要，包括巨噬细胞的募集和激活。这些募集和活化的白细胞引起病理性脂肪组织功能障碍（脂肪病），导致代谢异常。为了验证我们的假设，我们提出以下研究：1。确定各种脂肪酸对驻留脂肪组织细胞（包括脂肪细胞、T细胞和巨噬细胞）产生趋化因子的直接影响，并确定这种影响是否通过TLR2和/或TLR4激活。2. 确定两种重要的趋化因子通路（MCP-1/CCR2和RANTES/CCR5）对脂肪组织中T细胞/巨噬细胞募集和激活的贡献，并确定T细胞对富含SFAs的HF饮食小鼠脂肪组织炎症过程的贡献。3. 确定脂肪组织的机制？？T细胞和/或？T细胞直接改变前脂肪细胞或脂肪细胞的功能。公共卫生相关性：肥胖正在成为成人和儿童的全球流行病，并增加了患糖尿病和心血管疾病（CVD）的风险。心血管疾病已被证明是一种炎症性疾病，我们假设由高热量、高脂肪饮食引起的肥胖会增加身体的炎症反应。为了验证我们的假设，我们将研究饮食引起的肥胖对小鼠和人类脂肪细胞炎症相关因素的影响。