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Air pollution modulates brown adipose tissue function through epigenetic regulation by HDAC9 and KDM2B
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
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
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Research Article Cell biology Metabolism

Air pollution modulates brown adipose tissue function through epigenetic regulation by HDAC9 and KDM2B

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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

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Figure 1

Impaired glucose uptake and altered ultrastructure and secretory function of BAT induced by air pollution.

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Impaired glucose uptake and altered ultrastructure and secretory functio...
(A) FDG distribution in various peripheral tissues induced by insulin. Representative axial, coronal, sagittal images of mice from FA versus PM2.5 exposure (n = 4) are shown. PET/CT showing specific BATs that were assessed in this study (ROI placement in BAT in axial, coronal, and sagittal PET images and overlaid on CT images), and localization of specific tissues was established utilizing CT scans. Bar plots indicate mean FDG uptake level of BAT and other metabolic organs from mice exposed to FA versus PM2.5 (n = 4). (B) Representative TEM photomicrographs acquired from the section of the BAT from mice exposed to FA and PM2.5 for 24 weeks (n = 2). Bar plots represent mean mitochondrial number and size per image field. Higher magnification (scale bars: 0.5 μm) of mitochondria shows lamellar cristae in FA-exposed and tubular cristae structure in PM2.5-exposed mice. Lower magnification (scale bars: 2 μm) micrographs demonstrate the accumulation of lipid droplets in mitochondria. Bar plots represent the mean number of lipid droplets and their size per image field. Data were collected across 48 fields of view for 2 mice per group. (C) Heatmap indicates 24-hour circadian variation (ZT0 to ZT20) of thermogenic, metabolic, and antioxidant gene expression in BAT tissues (n = 3). Data are presented as fold change relative to the baseline (FA at ZT0) and the heatmap shows the mean value at each time point. Statistical significance was determined using an unpaired, 2-tailed Student’s t test, with P < 0.05 considered significant when comparing each ZT point between groups. (D) Describes the batokine mRNA expression levels in BAT from mice exposed to FA versus PM2.5 for 24 weeks (n = 5). Data are provided as mean ± SEM. *P < 0.05 versus FA-exposed mice by unpaired, 2-tailed Student’s t test.

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