Abstract
Recent experimental and epidemiologic data have strongly associated air pollution in the pathogenesis of insulin resistance and type 2 diabetes mellitus. We explored the effect of inhalational exposure to concentrated ambient particulate matter smaller than 2.5 μm (PM2.5), or filtered air, using a whole-body inhalation system (6 hours/day, 5 days/week) for 24 weeks on metabolism and brown adipose tissue (BAT) function. Mechanistic evaluation of insulin resistance, glucose uptake with 18F-fluorodeoxyglucose positron emission tomography, alongside evaluation for differentially methylated regions, chromatin accessibility, and differential expression of genes was performed. PM2.5 exposure impaired metabolism through changes in key BAT transcriptional programs involved in redox stress, lipid deposition, fibrosis, and altered thermogenesis. Significant differential methylation and widespread chromatin remodeling was noted in BAT with PM2.5. Integrated analysis uncovered a role for the histone deacetylase HDAC9 and histone demethylase KDM2B. The latter demethylates Lys-4 and Lys-36 of histone H3. Specifically, studies using ChIP combined with quantitative PCR confirmed HDAC9 and KDM2B occupancy and reduced H3K36me2 on the promoter of target BAT genes in PM2.5 mice, while Hdac9/Kdm2b knockdown and overexpression increased and reduced BAT metabolism, respectively. Collectively, our results provide insights into air pollution exposure and changes in BAT and metabolism.
Authors
Rengasamy Palanivel, Jean-Eudes Dazard, Bongsoo Park, Sarah Costantino, Skanda T. Moorthy, Armando Vergara-Martel, Elaine Ann Cara, Jonnelle Edwards-Glenn, Shyam Biswal, Lung Chi Chen, Mukesh K. Jain, Francesco Paneni, Sanjay Rajagopalan
Figure 9
Effect of siRNA-mediated knockdown and CRISPR/Cas9-mediated overexpression of
