1650-P: Chronic Air Pollution Induces Brown Adipose Dysfunction and Insulin Resistance through Epigenetic Modification of Key Metabolic Circadian and Redox Targets

Background: Prior studies have demonstrated a strong link between air pollution and type 2 diabetes including brown adipose tissue (BAT) dysfunction, common proximate regulators are poorly characterized. We hypothesized that exposure to ambient fine particulate matter (<2.5μm; PM_2.5) modulates insulin resistance through its impact on epigenetic regulators of BAT function.

Methods: Male C57BL/6 mice at the age of 4 weeks were fed a chow diet and exposed to concentrated PM_2.5 or filtered air (n = 12 per group) for 24 weeks (6hr/day and 5 days in a week) using a VACES system, that allows chronic exposure to real world air pollution. Glucose and insulin tolerance tests, indirect calorimetry using metabolic cages and PET/CT using 18-FDG uptake were performed between 12-20 weeks following air pollution exposure. BAT was isolated for DNA methylation (DMRs), chromatin accessibility (DARs), and Differentially Expressed Genes (DEGs) analysis using bisulfite, ATAC and RNA-sequencing respectively.

Results: BAT thermogenic activity was reduced by decreased FDG uptake (40%) with significant reduction in peak VO₂ and VCO₂ and RER at night time by PM_2.5. Genome wide differential methylation indicates evidence for hypomethylation and hypermethylation, with widespread chromatin remodeling involving intronic and enhancer elements corresponding to multiple transcription factor binding sites including genes involved in thermogenesis, redox and circadian function. Integrated DAR-DEG-DMR analysis pointed to two targets, a histone deacetylase-9 (HDAC9) and KDM2B, a lysine demethylase. ChIP-qPCR of HDAC9 and KDM2B revealed binding and regulation of RORα, GST1α and PRDM16 with HDAC9 and UCP1 and NRF2 with KDM2B, respectively.

Conclusion: Chronic air pollution exposure affects BAT function and induces insulin resistance through epigenetic regulation of key targets involved in redox function, thermogenesis and circadian function.