HDAC1 regulates thermogenic program via H3K27 deacetylation

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Project Abstract Obesity develops when a persistent imbalance between energy intake and energy expenditure occurs. Adaptive thermogenesis, in which brown adipose tissue (BAT) functions to dissipate energy as heat due to the unique expression of UCP1, is an integral part of overall energy expenditure. There are two types of brown adipocytes in rodents. Traditional brown adipocytes are located in discrete areas, whereas inducible beige adipocytes are dispersed in WAT and can be induced by cold exposure or β adrenergic activation. While numerous studies have been devoted to the evaluation of genetic factors in regulation of brown/beige cell function, much is unknown about epigenetic regulations including histone acetylation in this process. Evidence converges to suggest that epigenetic events, including histone acetylation, figure prominently in the development of obesity. Recent studies reported that class I HDAC inhibitor (HDACi) ameliorates obesity in mice. However, the exact member of the HDAC family and the precise mechanism whereby class I HDACi exerts these beneficial effects are not known. Histone deacetylase 1 (HDAC1) functions to remove acetyl groups from lysine residues in histone, thereby silencing gene expression. Our published and preliminary data suggest that HDAC1 deficiency promotes brown adipocyte thermogenic program and white adipocyte lipolysis via increasing histone lysine 27 (H3K27) acetylation (H3K27ac). Therefore, we hypothesize that HDAC1 regulates adaptive thermogenesis, lipolysis, energy metabolism and obesity in genetic models. Aim 1 will determine the role of HDAC1 in regulation of adaptive thermogenesis, energy metabolism and diet-induced obesity in genetic models. We have generated genetic mice with brown/beige adipocytes deficient or overexpressing HDAC1 and will characterize the phenotypes of cold-induced thermogenesis and diet-induced obesity in these mice. We will further investigate the orphan nuclear receptor NR4A1, identified via ChIP-Seq, as a downstream signal mediating H3K27ac-induced thermogenic program due to HDAC1 deficiency. Aim 2 will determine whether HDAC1 regulates lipolysis via a NR4A1-mediated lipolytic program. We have generated genetic models with fat (white and brown)-specific HDAC1 deletion or overexpression. We will determine: a) whether adipocyte-specific deletion of HDAC1 enhances, whereas specific overexpression of HDAC1 inhibits adipocyte lipolysis; b) whether enhanced H3K27ac by HDAC1 deficiency recruits NR4A1 to the lipolytic gene promoters, resulting in enhanced gene expression and subsequent lipolysis in white fat. Aim 3 will determine the molecular pathway whereby β adrenergic signal regulates HDAC1 activity. We will determine: a) β adrenergic activation disassociates a repressive complex consisting of HDAC1 and the co-repressors RIP140 and RB, which suppress the thermogenic program at basal state; and b) β adrenergic activation decreases HDAC1 activity via acetylation by the histone CBP. Our studies will shed new insights into identifying novel epigenetic targets for increasing brown/beige adipocytes in the treatment of obesity.