Air Pollution Epigenetically Rewires Brown Fat, Linking PM2.5 Exposure to Metabolic Dysfunction

A groundbreaking new study reveals that chronic exposure to fine particulate matter air pollution (PM2.5) significantly impairs brown adipose tissue (BAT) function through epigenetic mechanisms, potentially driving insulin resistance and increasing risk for type 2 diabetes mellitus (T2D). Researchers demonstrated that long-term inhalation of PM2.5 alters key transcriptional programs in BAT related to redox balance, lipid metabolism, thermogenesis, and fibrosis. This disruption occurs through widespread DNA methylation and chromatin remodeling, with two key epigenetic regulators—histone deacetylase 9 (HDAC9) and histone demethylase KDM2B—identified as critical mediators of these changes.

Using a controlled whole-body inhalation system, mice were exposed to PM2.5 or filtered air for 24 weeks. PET imaging revealed significantly reduced glucose uptake in BAT of PM2.5-exposed mice, accompanied by abnormal mitochondrial structure and lipid droplet accumulation. These physical changes correlated with decreased expression of thermogenic and metabolic genes, including Prdm16, Ucp1, and Pgc1a, and disturbed circadian regulation.

The study utilized integrative multi-omics—including DNA methylation, chromatin accessibility (ATAC-seq), and transcriptomics (RNA-seq)—to map the full scope of PM2.5's effects. Results showed 881 differentially methylated regions (DMRs), 2278 differentially accessible regions (DARs), and 663 differentially expressed genes (DEGs) in BAT following exposure. Notably, the majority of regulatory interactions between DMRs/DARs and DEGs occurred at distal (non-promoter) enhancer regions.

Through partial least squares (PLS) regression modeling, researchers identified HDAC9 and KDM2B as the only genes impacted across all epigenetic and transcriptomic layers. ChIP-qPCR confirmed their binding to key BAT gene promoters. Functional assays in brown adipocytes validated their causal role: overexpression of Hdac9 and Kdm2b suppressed glucose uptake, lactate production, and oxygen consumption, while their knockdown reversed these effects and boosted Ucp1 expression.

The findings reveal that HDAC9 and KDM2B epigenetically repress transcription of critical BAT genes such as Ucp1, Prdm16, and Nrf2—key regulators of thermogenesis, mitochondrial function, and antioxidant defenses. This repression is mediated through reduced histone acetylation and H3K36me2 methylation at target gene promoters.

Importantly, serum from PM2.5-exposed mice reproduced these effects in cultured BAT cells, demonstrating that circulating factors may also contribute to systemic epigenetic reprogramming. This study highlights the vulnerability of BAT to environmental insults and provides a mechanistic link between air pollution and metabolic disease risk. The identification of HDAC9 and KDM2B as key regulators opens new avenues for targeted epigenetic therapies aimed at restoring BAT function and metabolic health in polluted environments.