Obesity Development: Role of Air Pollution and High Fat Diet

描述（由申请人提供）：最近的研究表明，肥胖和饮食诱导脂肪组织炎症，这可能会促进2型糖尿病（T2 DM）和胰岛素抵抗（IR）的发展。流行病学研究表明，暴露于空气污染，特别是环境细颗粒物（<2.5？m，PM2.5），与心血管疾病的增加有关。我们最近的数据表明，短期暴露于吸入的PM2.5导致成年小鼠动脉粥样硬化的血管炎症。这种炎症反应可能是动脉粥样硬化、高血压和IR的基本机制之一。为了研究暴露于PM2.5对肥胖和IR发展的影响，我们假设PM2.5暴露诱导肥胖和IR发展，富脂饮食通过C-C基序趋化因子配体（CCL）2介导的脂肪组织巨噬细胞（ATM）加剧了肥胖和IR发展。浸润和增加的促炎经典活化（M1）/减少的抗炎交替活化（M2）小鼠内脏脂肪组织（VAT）中的巨噬细胞表型基因变化。为了验证这一假设，在第一个具体目标中，我们将研究暴露于PM2.5对小鼠从早期（4周龄）全身暴露系统中8周或24周的影响，检查肥胖的结果，巨噬细胞浸润的VAT，IR和血管功能障碍的C57 BL/6的低脂肪或高脂肪食物喂养的小鼠。将进行腹膜内葡萄糖耐量试验、体脂肪量磁共振成像、血管张力变化肌电描记术、IR骨骼肌、肝脏、皮下和内脏脂肪组织的形态学和免疫印迹以及脂肪细胞数量和大小定量。在第二个具体目标中，我们将确定PM2.5暴露诱导的肥胖和IR发展是否与VAT中的巨噬细胞浸润和M1/M2表型基因表达变化相关。在最后的具体目标中，我们将说明PM2.5诱导的肥胖和IR是由CCL 2介导的，通过ATM激活，募集和M1/M2表型基因表达的变化，在C-C基序趋化因子受体（CCR）2-/-小鼠的VAT。通过使用最先进的真实的世界PM2.5暴露与炎症机制的最新进展，该提案提供了一个前所未有的机会来阐明PM2.5对肥胖，T2 DM和IR发展的影响的生理相关机制，其中每一个都对公共健康有重大影响。公共卫生相关性：空气污染和肥胖都造成重大的公共卫生负担。这项研究将检查暴露于环境细颗粒物污染结合高脂肪饮食是否会共同作用，导致肥胖，2型糖尿病和胰岛素抵抗增加。

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.