Abstract
Brown adipocytes function to dissipate energy as heat through adaptive thermogenesis. Understanding the molecular mechanisms underlying the brown fat thermogenic program may provide insights for the development of therapeutic approaches in the treatment of obesity. Most studies investigating the mechanisms underlying brown fat development focus on genetic mechanisms; little is known about the epigenetic mechanisms in this process. We have discovered that ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), a histone demethylase for di- or tri-methylated histone 3 lysine 27 (H3K27me2/3), plays a potential role in regulating brown adipocyte thermogenic program. We found that UTX is up-regulated during brown adipocyte differentiation and by cold exposure in both brown adipose tissue (BAT) and white adipose tissue (WAT) of mice, suggesting a potential role in thermogenesis. Inactivation of UTX down-regulates brown fat specific gene expression, while overexpression of UTX does the opposite. Notably, activation of β adrenergic signaling recruits UTX to the UCP1 and PGC1α promoters, leading to decreased H3K27me3, a histone transcriptional repressive mark. UTX demethylates H3K27me3 and subsequently interacts with the histone acetyltransferase (HAT) protein CBP, resulting in increased H3K27 acetylation (H3K27ac), a histone transcriptional active mark. UTX positively regulate brown adipocyte thermogenic program through coordinated control of demethylating H3K27me3 and acetylating H3K27, switching the transcriptional repressive state to the transcriptional active state at the promoters of UCP1 and PGC1α. We conclude that UTX may play a potential role in regulation of brown adipocyte gene expression and may mediate β adrenergic activation of brown fat function.
Highlights
Brown fat functions to dissipate energy through adaptive thermogenesis
We found that both UTX mRNA and protein levels displayed a slow but sustained increase during the course of BAT1 adipocyte differentiation (Fig. 1, D and E)
We measured UTX mRNA and protein expression in both brown adipose tissue (BAT) and white adipose tissue (WAT) of C57BL/6J mice. We found that both UTX mRNA and protein levels were higher in BAT than in WAT (Fig. 2, A and B)
Summary
Results: The histone demethylase UTX positively regulates brown fat thermogenic program. We have discovered that ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX), a histone demethylase for di- or tri-methylated histone 3 lysine 27 (H3K27me2/3), plays a potential role in regulating brown adipocyte thermogenic program. We conclude that UTX may play a potential role in regulation of brown adipocyte gene expression and may mediate  adrenergic activation of brown fat function. UTX Regulates Brown Fat Gene Expression that increasing functional brown/beige adipocytes in humans is a novel and promising target in treating obesity. To identify functional epigenetic marks that regulate brown fat development and function, we knocked down most enzymes that catalyze histone methylation and acetylation, including histone methyltransferases and demethylases and used UCP1 expression as a readout in brown adipocytes BAT1. We examined the methylation of H3K27 at UCP1 and PGC1 promoter/enhancer regions and the interaction among key molecules responsible for the methylation and acetylation of H3K27, including polycomb repressive complex 2 (PRC2) and CREBbinding protein (CBP)
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