A distal enhancer of Pparα regulates thermogenesis and mitochondrial function in brown fat

作者：Tingting Jiang, Danhong Su, Jing Ke, Xin Dai, Maohua Wang, Yan Wang, Siyuan Zhan, Tao Zhong, Jiazhong Guo, Li Li, H.P. Zhang, Linjie Wang · 发表于：PLoS Genetics · 年份：2025 · DOI：10.1371/journal.pgen.1011915 · 被引用次数：3 · 研究领域：Adipose Tissue and Metabolism、Lipid metabolism and biosynthesis、Peroxisome Proliferator-Activated Receptors

Peroxisome proliferator-activated receptor α (PPARα) is a crucial transcription factor in regulating brown adipose tissue (BAT) physiological function. However, the mechanisms of enhancer-promoter chromatin interactions that control transcription regulation of Pparα in BAT remain unclear. In this study, we used circularized chromosome conformation capture coupled with next-generation sequencing (4C-seq) to reveal distinct differences in Pparα-associated chromatin interactions between intrascapular BAT (iBAT) and epididymal white adipose tissue (eWAT). In addition, we identified an iBAT-specific active enhancer (Pparα-En4) that was activated by cold stimulation. Functional assays demonstrated that targeted repression of Pparα-En4 region significantly decreased Pparα expression and impaired brown adipocyte differentiation and thermogenesis. Moreover, the transcription factor CREB regulated Pparα-En4 activity and increased Pparα expression in cooperation with the acetyltransferase CBP. Repression of Pparα-En4 using a lentiviral system in iBAT resulted in reduced thermogenic capacity and mitochondrial damage during cold acclimation conditions in vivo. These findings reveal that Pparα-En4 is a critical regulatory element in thermogenesis and mitochondrial function, and provide important insights into enhancer-mediated transcriptional regulation of Pparα expression in BAT.