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: 8452140
• 负责人: CHRISTIE Mitchell BALLANTYNE
• 金额: $ 30.97万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452140
• 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; Health; 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; 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.

描述（由申请人提供）：肥胖增加了患糖尿病和心血管疾病（CVD）的风险。脂肪组织炎症增加，随着趋化因子和细胞因子表达和巨噬细胞的积累增加，有助于脂肪组织功能障碍，胰岛素抵抗以及糖尿病和CVD的发育。使用富含饱和脂肪酸（SFAS）的高脂饮食诱导的肥胖小鼠模型，我们使新的发现T细胞增加了，趋化因子对激活进行了调节，正常的T细胞表达并分泌（ rantes）及其受体CCR5以及单核细胞化学吸引蛋白-1（MCP-1）和受体CCR2，在肥胖胰岛素耐药小鼠的脂肪组织和人内脏脂肪组织中上调。两个都 ？？ T细胞和?? T细胞居住在瘦小鼠的脂肪组织中。与瘦小小鼠相比，肥胖小鼠显着增加？ T细胞，但不在？脂肪组织中的T细胞。高sFA饮食引起的脂肪发育的早期，脂肪组织的rantes和MCP-1增加。棕榈酸是HF饮食中高浓度的长链SFA，在体外增加了MCP-1，并在脂肪细胞中增加了表达。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？小鼠中的T细胞减少了HF饮食诱导的脂肪组织炎症。活化的T细胞抑制前脂肪细胞到脂肪细胞的分化，并显着降低脂肪细胞中甘油三酸酯的积累，并诱导脂肪细胞炎症。炎症对脂肪组织功能的影响，例如随着FA沉积减少的FA代谢改变并通过脂肪细胞释放的FA增加，可能会增加肝脏的自由FA通量，导致异位脂肪沉积和增加肝和全身性炎症，并增加糖尿病和CVD。我们假设在HF饮食引起的肥胖性发展时，饮食SFA激活脂肪剂驻留细胞（脂肪细胞/脂肪细胞/前脂肪细胞，T细胞和巨噬细胞），以产生趋化和激活T细胞的趋化因子，以及T细胞对T细胞至关重要脂肪组织中炎症变化的变化，包括募集和激活巨噬细胞。这些招募和活化的白细胞引起病理脂肪组织功能障碍（脂肪症），导致代谢异常。为了检验我们的假设，我们提出了以下研究：1。确定各种脂肪酸对居民脂肪组织细胞（包括脂肪细胞，T细胞和巨噬细胞）的趋化因子产生的直接影响，并确定这种影响是否导致通过TLR2和/或TLR4。 2。确定两种突出的趋化因子途径（MCP-1/CCR2和RANTES/CCR5）对脂肪组织中T细胞/巨噬细胞的募集和激活的贡献，并确定T细胞对小鼠脂肪组织在小鼠脂肪组织中炎症过程的贡献富含SFA的HF饮食。 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功能。

项目成果

Essential role of CD11a in CD8+ T-cell accumulation and activation in adipose tissue.

• DOI: 10.1161/atvbaha.113.302077
• 发表时间: 2014-01
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Jiang E;Perrard XD;Yang D;Khan IM;Perrard JL;Smith CW;Ballantyne CM;Wu H
• 通讯作者: Wu H

Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity.

• DOI: 10.1016/j.atherosclerosis.2011.07.025
• 发表时间: 2011-11
• 期刊: ATHEROSCLEROSIS
• 影响因子: 5.3
• 作者: Wang, Qun;Perrard, Xiaoyuan Dai;Perrard, Jerry L.;Mansoori, Amir;Raya, Joe L.;Hoogeveen, Ron;Smith, C. Wayne;Ballantyne, Christie M.;Wu, Huaizhu
• 通讯作者: Wu, Huaizhu

Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity.

• DOI: 10.1038/oby.2010.213
• 发表时间: 2011-03
• 期刊: Obesity (Silver Spring, Md.)
• 作者: Wang Q;Perrard XD;Perrard JL;Mansoori A;Smith CW;Ballantyne CM;Wu H
• 通讯作者: Wu H

Inflammation, adipose tissue, and T cells: what is the "straight skinny" on lean versus fat mice?

炎症、脂肪组织和 T 细胞：瘦小鼠与胖小鼠的“瘦”是什么？

• DOI: 10.1161/circresaha.109.201244
• 发表时间: 2009
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Wu,Huaizhu;Ballantyne,ChristieM
• 通讯作者: Ballantyne,ChristieM