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.
Overweight and obesity cause significant public health burdens. This study will examine whether exposure to particulate air pollution causes increased inflammation in adipose tissues, induces adiposity in visceral fat tissue and vascular dysfunction and imbalance white and brown adipose.
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