Obesity Development: Role of Air Pollution and High Fat Diet

肥胖的发展：空气污染和高脂肪饮食的作用

• 批准号: 8074222
• 负责人: Qinghua Sun
• 金额: $ 2.05万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074222
• 关键词: Acetylcholine; Adipocytes; Adipose tissue; Adult; Age; Air Pollution; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Atherosclerosis; Biochemical; Biological Assay; Blood; Blood Vessels; Body fat; Breathing; C57BL/6 Mouse; CCL2 gene; Caliber; Cardiovascular Diseases; Cell Fraction; Chemotaxis; Coupled; Cytolysis; Data; Development; Diet; Endothelium; Endothelium-Dependent Relaxing Factors; Enzyme-Linked Immunosorbent Assay; Eosine Yellowish; Epidemiologic Studies; Evaluation; Exposure to; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Glucose tolerance test; Hematoxylin; Hypertension; Immunoblotting; Immunofluorescence Immunologic; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Leptin; Ligands; Liver; Macrophage Activation; Magnetic Resonance Imaging; Measurement; Mediating; Monocyte Chemoattractant Protein-1; Morphology; Mus; Nitroglycerin; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Particulate; Particulate Matter; Pathway interactions; Phenylephrine; Plasma; Pollution; Procedures; Public Health; RNA; Relaxation; Research; Resistance development; Role; Skeletal Muscle; Staining method; Stains; System; Testing; Time; Tissues; Vasomotor; Visceral; adiponectin; air filter; chemokine; chemokine receptor; constriction; feeding; intraperitoneal; macrophage; public health relevance; response; subcutaneous; vascular inflammation

DESCRIPTION (provided by applicant): Recent research suggests that obesity and diet induce inflammation in adipose tissue, which may enhance the development of type 2 diabetes mellitus (T2DM) and insulin resistance (IR). Epidemiological studies have demonstrated that exposure to air pollution, in particular ambient fine particulate matter (<2.5 ?m, PM2.5), is associated with increased cardiovascular diseases. Our recent data have shown that short-term exposure to inhaled PM2.5 results in vascular inflammation in atherosclerosis in adult mice. This inflammatory response may represent a key integrative pathway that is one of the fundamental mechanisms for atherosclerosis, hypertension, and IR. To investigate the effects of exposure to PM2.5 on adiposity and IR development, we hypothesize that PM2.5 exposure induces adiposity and IR development that is exaggerated by fat-rich diet through C-C motif chemokine ligand (CCL)2-mediated adipose tissue macrophage (ATM) infiltration and increased pro-inflammatory classically activated (M1)/ decreased anti-inflammatory alternatively activated (M2) macrophage phenotypic gene change in visceral adipose tissue (VAT) in mice. To test this hypothesis, in the first specific aim, we will investigate the effect of exposure to PM2.5 on mice in a whole body exposure system from early age (4 weeks old) for 8 or 24 weeks, examining outcomes of adiposity, macrophage infiltration in VAT, IR, and vascular dysfunction in C57BL/6 for mice fed with either low fat or high fat chow. Intraperitoneal glucose tolerance test, magnetic resonance imaging on body fat mass, myograph on vasomotor tone change, morphology and immunoblotting of skeletal muscle, liver, subcutaneous and visceral adipose tissues on IR, and adipocyte number and size quantification will be performed. In the second specific aim, we will determine whether the adiposity and IR development induced by PM2.5 exposure is associated with macrophage infiltration and M1/M2 phenotypic gene expression change in VAT. In the final specific aim, we will illustrate that PM2.5-induced adiposity and IR is mediated by CCL2 via ATM activation, recruitment, and M1/M2 phenotypic gene expression change in the VAT in C-C motif chemokine receptor (CCR)2-/- mice. By using state-of-the-art real world PM2.5 exposure in conjunction with the latest advances in inflammatory mechanisms, this proposal provides an unprecedented opportunity to elucidate physiologically relevant mechanisms responsible for the effects of PM2.5 on the development of obesity, T2DM, and IR, each of which has significant impact on public health. PUBLIC HEALTH RELEVANCE: Air pollution and obesity each cause significant public health burdens. This study will examine whether exposure to ambient fine particulate pollution combined with a high fat diet will act together to cause increased obesity, type 2 diabetes mellitus, and insulin resistance.

描述（由申请人提供）：最近的研究表明，肥胖和饮食会诱导脂肪组织的炎症，这可能会增强2型糖尿病的发展（T2DM）（T2DM）和胰岛素抵抗（IR）。流行病学研究表明，暴露于空气污染，特别是环境细胞质物质（<2.5？m，pm2.5）与心血管疾病增加有关。我们最近的数据表明，短期暴露于成年小鼠的动脉粥样硬化导致动脉粥样硬化的血管炎症。这种炎症反应可能代表着关键的综合途径，这是动脉粥样硬化，高血压和IR的基本机制之一。为了研究暴露于PM2.5对肥胖性和IR发育的影响，我们假设PM2.5暴露会通过C-C-C-C-C-C型趋化因子配体（CCL）2-介导的脂肪型脂肪组织（CCL）2-介导的脂肪症组织（ATM）渗透（ATM）渗透（ATM）延伸，并增加了经常激活（M1）的脂肪饮食（CCL）2-介导的脂肪饮食（M1），这会引起脂肪和IR发育的影响（M1）。小鼠内脏脂肪组织（VAT）中巨噬细胞表型基因的变化。为了检验这一假设，在第一个具体目的中，我们将研究从早期（4周龄）持续8或24周的整个身体暴露系统中暴露于PM2.5的影响，研究肥胖，巨噬细胞的巨噬细胞浸润，IR，IR和血管功能障碍的巨噬细胞浸润，以及对C57BL/6的血管功能障碍，对C57BL/6的脂肪含量低或高脂肪或高脂肪或高脂肪的脂肪。腹膜内葡萄糖耐量试验，体内脂肪质量上的磁共振成像，有关血管肌张力的变化，形态和骨骼肌的免疫印迹，肝脏，皮下和内脏脂肪组织在IR上的内脏和内脏脂肪组织以及脂肪细胞数量和脂肪数量和尺寸定量。在第二个特定目的中，我们将确定PM2.5暴露引起的肥胖和IR发育是否与巨噬细胞浸润和M1/M2表型基因表达在增值税中的变化有关。在最终的具体目的中，我们将说明PM2.5诱导的肥胖和IR是由CCL2通过ATM激活，募集和M1/M2表型基因表达在C-C基序趋化因子受体（CCR）2 - / - 小鼠中的增值税中介导的。通过使用最新的现实世界PM2.5与炎症机制的最新进展结合使用，该提案提供了一个前所未有的机会，可以阐明负责PM2.5对肥胖，T2DM和IR的影响的生理相关机制，这些机制对公共健康产生了重大影响。公共卫生相关性：空气污染和肥胖均会造成巨大的公共卫生负担。这项研究将检查暴露于环境细胞颗粒污染与高脂肪饮食的结合是否会导致肥胖，2型糖尿病和胰岛素抵抗。