Childhood obesity rates have increased for four decades, leading to increased prevalence of non-alcoholic fatty liver disease and type 2 diabetes in children and to substantial morbidity and mortality due to associated metabolic disease in adults. Emerging evidence indicates that the inflammatory profile of adipose tissue is an important determinant of the development of systemic inflammation, insulin resistance and metabolic disease in obese populations. Recent experimental work suggests that inhaled ambient particulate matter less than 5 pm in aerodynamic diameter {PMzs) causes similar metabolic effects in obese mice. New results from our Children's Health Study {CHS) show that near-roadway air pollution {NRAP) is strongly associated with childhood obesity and growth trajectory of body mass index. This project will investigate the mechanisms underlying NRAP associations with adipose tissue distribution and systemic metabolic outcomes in a subset of overweight and obese subjects understudy in Project 1 {PI). Associations of NRAP PM exposure with adipose tissue inflammation and insulin resistance, and the role of adipose tissue inflammation in the systemic metabolic effects of exposure, will be studied using deep subcutaneous abdominal adipose tissue {SAT) obtained by an innovative biopsy procedure from 60 overweight CHS participants. The subjects will be selected to represent the extremes of NRAP exposure occurring in Southern California and will be a subset of PI participants. The CHS was designed to evaluate the health effects of air pollution and the cohort (n=4560) has been followed prospectively over the course of childhood from age 6-18 years. Lifetime exposure to NRAP PM2.5 elemental carbon {EC) and transition metals (Fe and Cu) composition from birth to age 18 will be estimated from geocoded residential and school address history. A validated model of exposure has been developed using a unique historical data set of measurements of these pollutants in CHS communities and traffic distance, volume, meteorology and other land use variables. EC and these metals were selected for study because their known pro-inflammatory effects and steep near-roadway gradients make them likely causal components responsible for inflammatory and metabolic effects ofthe NRAP pollution mixture. In preliminary results generated for this application using a separate convenience sample of 36 obese young adults, modeled exposure to cruder markers ofthe NRAP mixture was associated with SAT inflammatory profile and with inflammatory gene expression. These results suggest that exposure to NRAP is associated with adipose tissue inflammation, which could play a critical role in promoting systemic inflammation, insulin resistance, and the metabolic risk associated with obesity. To our knowledge, these relationships have not previously been studied in humans. For this project, CHS participants from the extremes of lifetime cumulative NRAP exposure over childhood will be recruited as they reach age 18. Associations of EC and metals with inflammatory {Ml) macrophages determined by flow cytometry in SAT and with inflammatory cytokine and adipokine release from fat biopsies incubated ex vivo will be assessed. Based on preliminary results and relevant literature, the impact of exposure on expression of selected genes involved in inflammation and in insulin sensitivity will be investigated in macrophages and adipocytes, respectively. Innovative statistical modeling techniques will be used to examine the inflammatory mechanisms underlying NRAP effects on body fat, adipose inflammation, and metabolic outcomes. This analysis will use additional data on MRI hepatic and abdominal visceral adipose distribution, systemic inflammation and insulin resistance from P I , and covariates from the entire CHS cohort.
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