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

描述（由申请人提供）：由于肥胖症的增加，发达国家的预期寿命可能首次开始下降。环境因素越来越多地被发现与肥胖的发展有关。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）依赖性激活内质网（ER）应激和增强胰岛素抵抗诱导脂肪功能障碍。为了实现这一目标，我们首先评估PM2.5诱导的内脏ER应激，（白色脂肪组织）和血管周围组织在野生型（C57 BL/6）和CHOP[CCAAT/增强子结合蛋白（C/EBP）同源蛋白]-/-小鼠中在野生型和CHOP-/-小鼠中在全身暴露系统中的脂肪血管功能障碍的增强“俄亥俄州的空气污染暴露系统，用于询问全身效应（OASIS）-1”长达24周。将进行磁共振成像（MRI）以评价体脂质量/分布，正电子发射断层扫描和计算机断层扫描（microPET-CT）以评价棕色脂肪组织的活性，组织组织学检查以评估线粒体含量、脂肪细胞增生和肥大以及脂肪组织中的血管生长，肌电描记术以研究大血管功能。还将评估脂肪组织的PERK介导的UPR途径对线粒体功能、炎症和细胞凋亡的影响。将含镍的PM2.5或含钒的PM2.5与单独的PM2.5暴露进行比较，以评价生物反应的差异。然后，我们研究PM2.5暴露诱导的巨噬细胞ER应激反应是否是脂肪炎症和功能障碍的核心，通过流式分选和激光捕获显微镜，并评估ER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）的指数。将通过向未暴露的裸鼠中注射CD 24+、CD 24-或CD 34+细胞或与脂肪组织巨噬细胞联合进行脂肪组织重建，进行体内脂肪形成试验。最后，我们研究了PM2.5是否通过激活PERK-eIF 21-CHOP通路的未折叠蛋白反应（UPR）和内质网（ER）应激来诱导NAD（P）H氧化酶关键组分缺陷的p47 phox-/-和gp 91 phox-/-小鼠的改变。因此，我们打算把重点放在脂肪组织，但系统地，机械地研究单核细胞/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，我们模拟了人类从儿童到成年的肥胖发展。该提案的研究结果有望为更好地了解空气污染暴露对肥胖发展和相关血管功能障碍的机制做出重大贡献，这可能导致更绿色能源工厂和汽车的新政策/干预措施，更严格的空气质量标准，以及更好的全面肥胖预防。

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.