Obesity Development: Role of Air Pollution and High Fat Diet

描述(申请人提供)：最近的研究表明，肥胖和饮食会导致脂肪组织的炎症，这可能会增加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，特别是环境中的细颗粒物(&lt；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PM2.5会导致成年小鼠动脉粥样硬化的血管炎症。这种炎症反应可能代表了一个关键的整合途径，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对肥胖和胰岛素抵抗的影响，我们假设PM2.5暴露通过C-C基序趋化因子配体(CCL)2介导的脂肪组织巨噬细胞(ATM)的渗透和增加促炎性经典激活(M1)/减少抗炎选择性激活(M2)巨噬细胞表型基因改变来诱导肥胖和IR的发生。为了验证这一假说，在第一个特定目标中，我们将研究PM2.5对小鼠从早期(4周大)全身暴露系统中8或24周的影响，检查肥胖、VAT中巨噬细胞浸润、IR和C57BL/6中血管功能障碍的结果。将进行腹膜糖耐量试验、体脂核磁共振成像、血管舒张性张力变化肌图、骨骼肌、肝脏、皮下和内脏脂肪组织IR的形态和免疫印迹，以及脂肪细胞数量和大小的定量。在第二个特定目标中，我们将确定PM2.5暴露诱导的肥胖和IR的发生是否与VAT中巨噬细胞的浸润和M1/M2表型基因表达的变化有关。在最终的特定目标中，我们将阐明PM2.5诱导的肥胖和IR是由CCL2通过ATM激活、募集和C-C基序趋化因子受体(CCR)2-/-小鼠VAT中M1/M2表型基因表达的变化而介导的。通过将现实世界最先进的PM2.5暴露与炎症机制的最新进展结合起来，这项提议提供了一个前所未有的机会来阐明PM2.5对肥胖、T2 DM和IR的影响的生理相关机制，这些机制中的每一个都对公共健康有重大影响。与公共健康相关：空气污染和肥胖都会造成重大的公共健康负担。这项研究将研究暴露在环境中的细颗粒物污染和高脂肪饮食是否会共同导致肥胖、2型糖尿病和胰岛素抵抗的增加。

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.