PCB-126 exposure promotes brown adipose tissue dysfunction and metabolic inflexibility in mice.

Polychlorinated biphenyls (PCBs) remain a global health concern due to their persistence and toxicity. PCB-126, a potent aryl hydrocarbon receptor (AhR) agonist, is linked to metabolic disruption, yet its impact on brown adipose tissue (BAT) is not fully understood. Male C57BL/6 mice were exposed to PCB-126 (5 µmol/kg) for 10 weeks, followed by morphological, biochemical, and molecular interscapular brown adipose tissue (iBAT) analyses. Despite comparable energy intake and delta body weight, PCB-126 markedly increased relative visceral fat and reduced relative iBAT mass. Oral glucose tolerance testing revealed impaired glucose handling, with higher glycemia across the curve and a ~ 30% increase in AUC, indicating systemic metabolic dysfunction. Histology showed extensive lipid droplet remodeling—reduced lipid area fraction but increased droplet number—consistent with a blunted thermogenic phenotype. At the molecular level, PCB-126 downregulated thermogenic markers (Ucp1, Prdm16, Pgc-1α, Adrb3) and Vegfa, reflecting impaired vascularization. Genes involved in lipid droplet regulation (Cidea), adipogenic control (Pparγ), and energy-sensing (Ampk2) were also suppressed, reinforcing thermogenic loss and reduced metabolic flexibility. These changes coincided with heightened inflammation (Tnf-α, Il-6), oxidative stress (↑MDA, ↑NOx), and compromised antioxidant defenses (↓SOD, ↓catalase, ↑GPx). Overall, PCB-126 disrupts BAT structure and transcriptional programming, impairs glucose tolerance, and promotes visceral fat accumulation through combined thermogenic, inflammatory, and redox dysregulation.