Air Pollution on Adiposity and Vascular Dysfunction: White or Brown Matters?

描述（由申请人提供）：由于肥胖的增加，发达国家的预期寿命可能首次开始下降。人们越来越多地发现环境因素与肥胖的发生有关。为了研究空气污染暴露是否会导致脂肪组织的肥胖和炎症，从而诱导胰岛素抵抗和血管功能障碍，我们假设暴露于细颗粒物（PM2.5）污染通过活性氧（ROS）依赖的内质网（ER）应激激活和胰岛素抵抗增强来诱导脂肪功能障碍。为了实现这一目标，我们首先评估了pm2.5在内脏（白色脂肪组织）和血管周围组织（棕色脂肪组织）中诱导的内质网应激，以及野生型（C57BL/6）和CHOP[CCAAT/增强子结合蛋白（C/EBP）同源蛋白]-/-小鼠（野生型）和CHOP-/-小鼠（全身暴露系统“俄亥俄州空气污染暴露系统对系统效应的调查(OASIS)-1”）中长达24周的脂肪血管功能障碍的增强。磁共振成像（MRI）评估体脂肪质量/分布，综合正电子发射断层扫描和计算机断层扫描（微pet - ct）评估棕色脂肪组织的活性，组织组织学检查评估线粒体含量，脂肪细胞增生和肥大，以及脂肪组织中的血管生长，肌图调查大血管功能。脂肪组织也将被评估perk介导的UPR通路对线粒体功能、炎症和凋亡的影响。将含镍PM2.5或含钒PM2.5与单独接触PM2.5进行比较，以评估生物反应的差异。然后，我们通过流动分选和激光捕获显微镜研究PM2.5暴露诱导巨噬细胞内质网应激反应是否是脂肪炎症和功能障碍的核心，并评估内质网应激和凋亡、线粒体含量、关键线粒体基因表达和线粒体耗氧量（功能）等指标。体内脂肪生成实验将通过细胞注射CD24+、CD24-或CD34+进行脂肪组织重建，或与脂肪组织巨噬细胞联合进入未暴露的裸鼠。我们最终研究了pm2.5是否通过未折叠蛋白反应（UPR）激活和内质网（ER）应激的PERK-eIF21-CHOP途径，诱导NAD(P)H氧化酶关键成分缺乏的p47phox-/-和gp91phox-/-小鼠发生改变。因此，我们打算将重点放在脂肪组织上，但系统地、机制地研究单核细胞/巨噬细胞在空气污染诱导的肥胖和血管功能障碍中的作用。通过在小鼠4周龄时开始暴露并暴露至24周龄，我们模拟了人类从童年到成年的肥胖发展。该研究结果有望为进一步了解空气污染暴露对肥胖发展和相关血管功能障碍的影响机制做出重要贡献，这可能有助于制定更环保的能源工厂和汽车的新政策/干预措施，制定更严格的空气质量标准，更好地全面预防肥胖。

DESCRIPTION (provided by applicant): Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time. Environmental factors are increasingly found to be associated with the development of obesity. To investigate if air pollution exposure contributes to adiposity and inflammation in adipose tissues that induces insulin resistance and vascular dysfunction, we hypothesize that exposure to fine particulate matter (PM2.5) pollution induces adipose dysfunction via reactive oxygen species (ROS)-dependent activation of endoplasmic reticulum (ER) stress and potentiation of insulin resistance. To achieve this goal, we first assess PM2.5-induced ER stress in visceral (white adipose tissue) and perivascular tissue (brown adipose tissue) and potentiation of adipose vascular dysfunction in wild type (C57BL/6) and CHOP[CCAAT/enhancer binding protein (C/EBP) homologous protein]-/- mice in wild type and CHOP-/- mice in a whole body exposure system "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1" up to 24 weeks. Magnetic resonance imaging (MRI) to evaluate body fat mass/distribution, integrated positron-emission tomography and computed tomography (microPET-CT) to evaluate the activity of brown adipose tissue, tissue histological examination to assess mitochondria content, adipocyte hyperplasia and hypertrophy, and vascular growth in the fat tissues, myograph to investigate macrovascular function will be performed. Fat tissues will also be assessed for PERK-mediated UPR pathway on mitochondrial function, inflammation and apoptosis. PM2.5 with Nickel or PM2.5 with vanadium will be compared to PM2.5 exposure alone to evaluate differences in biological responses. We then investigate if PM2.5 exposure induced ER stress response in macrophages is central to adipose inflammation and dysfunction by flow sorting and laser capture microscopy and assessed for indices for ER stress and apoptosis, mitochondria content, expression of key-mitochondrial genes and mitochondrial oxygen consumption (function). An in vivo adipogenesis assay will be performed by adipose tissue reconstitution via cell injection of CD24+, CD24-, or CD34+, or combined with adipose tissue macrophages into non-exposed nude mice. We finally study if PM2.5-induced alteration in p47phox-/- and gp91phox-/- mice that are deficient in critical component of NAD(P)H oxidase through unfolded protein response (UPR) activation and endoplasmic reticulum (ER) stress of PERK-eIF21-CHOP pathway. Therefore, we intend to focus on adipose tissues but systemically, mechanistically investigate the role of monocyte/macrophage in air pollution-induced adiposity and vascular dysfunction. By starting the exposure at age of 4 weeks in mice and exposure up to 24 weeks, we mimic the obesity development from childhood to adulthood in human. The findings from this proposal are expected to make significant contribution to better understanding the mechanisms of air pollution exposure on obesity development and associated vascular dysfunction, which may lead to the new policies/interventions in greener energy plants and automobiles, stricter air quality standards, and better, comprehensive obesity prevention.