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

TL;DR

This study identifies a specific enhancer that regulates PPARα in brown fat, impacting thermogenesis and mitochondrial function.

Contribution

The discovery of a BAT-specific enhancer (Pparα-En4) regulated by CREB and CBP, which controls PPARα expression and thermogenesis.

Findings

The enhancer Pparα-En4 is activated by cold and regulates PPARα expression in brown fat.

Repression of Pparα-En4 impairs brown adipocyte differentiation and mitochondrial function.

CREB and CBP cooperate to regulate Pparα-En4 activity and PPARα expression.

Abstract

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.

Brown adipose tissue (BAT) converts chemical energy into heat through the action of mitochondrial uncoupling protein 1. The thermogenic program in adipocytes is governed by a complex network of transcription factors and associated regulatory proteins. PPARα functions as a key transcription factor involved in the thermogenic program. Enhancers serve as pivotal cis-regulatory elements that modulate gene expression by establishing physical interactions with their target promoters mediated by transcription factor-protein complexes. Here, we identify a BAT-specific enhancer of Pparα (Pparα-En4) that regulates thermogenesis and mitochondrial integrity of BAT. The activity of Pparα-En4 is regulated by CREB in cooperation with the acetyltransferase CBP. These findings provide important insights into enhancer-mediated transcriptional regulation in BAT.

Figures