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

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 2

Impaired glucose clearance and metabolic rate induced by air pollution.

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Impaired glucose clearance and metabolic rate induced by air pollution. ...
(A) Glucose tolerance tests in FA- versus PM2.5-exposed mice (n = 16/group). After an overnight fast, an i.p. glucose load (2 g/kg) was given to FA- and PM2.5-exposed mice. (B) Insulin tolerance tests were done on 6-hour-fasted mice using an i.p. injection of 0.75 U/kg regular human insulin and blood glucose levels were monitored as indicated in the figures. The AUC of glucose and insulin tolerance test results and corresponding average body weight are shown in the bar plots. Energy expenditure, respiratory exchange ratio (RER), and physical activity were measured by indirect calorimetry in C57BL/6J mice after 20 weeks of exposure to FA or PM2.5. (C) Energy expenditure was calculated from measured VO2 and RER. It is shown respective to body weight for each exposure group as an average over a 72-hour period. Day period is represented by white background and night period by gray background. The corresponding bar plots indicate average total day and night energy expenditure. VO2 (D), VCO2 (E), RER (F), and physical parameters such as, activity level (G), food and water intake (H), and water consumption (I) are shown as average over a 72-hour period. Corresponding bar plots show average day and night total VO2, VCO2, and RER, activity, food and water intake values of the FA and PM2.5 groups. Metabolic cage study, all parameters, n = 8/group. Data are provided as mean ± SEM. *P < 0.05 versus FA-exposed mice by unpaired, 2-tailed Student’s t test.