Inactivation of Histone Deacetylase 1 (HDAC1) But Not HDAC2 Is Required for the Glucocorticoid-Dependent CCAAT/Enhancer-Binding Protein α (C/EBPα) Expression and Preadipocyte Differentiation

Abstract

Several drugs currently used in the management of mood disorders, epilepsy (ie, valproic acid), or the control of inflammation (ie, corticosteroids) have been shown to promote visceral obesity in humans by increasing the number of newly formed adipocytes. Valproic acid is classified as a nonspecific histone deacetylase (HDAC) inhibitor, along with trichostatin A and butyric acid. In vitro experiments have demonstrated that such molecules greatly enhance the rate of preadipocyte differentiation, similarly to the effect of corticosteroids. The glucocorticoid receptor stimulates adipogenesis in part by enhancing the transcription of C/ebpa through the titration, and subsequent degradation, of HDAC1 from the C/ebpα promoter. There is, however, controversy in the literature as to the role of HDACs during adipogenesis. In this study, we sought to demonstrate, using 2 different strategies, the definite role of HDAC1 in adipogenesis. By using small interference RNA-mediated knockdown of HDAC1 and by generating an enzymatically inactive HDAC1D181A by site-directed mutagenesis, we were able to show that HDAC1, but not HDAC2, suppresses glucocorticoid receptor-potentiated preadipocyte differentiation by decreasing CCAAT/enhancer-binding protein (C/ebp)α and Pparγ expression levels at the onset of differentiation. Finally, we demonstrate that HDAC1D181A acts as a dominant negative mutant of HDAC1 during adipogenesis by modulating C/EBPβ transcriptional activity on the C/ebpα promoter.

Cold exposure drives weight gain and adiposity following chronic suppression of brown adipose tissue

“…In BAT, this is associated with an enrichment of GO terms associated with DNA metabolism (i.e. histone deacetylation) with CTBP1, HDAC1 and SIRT2 all previously shown to be negative regulators of lipogenesis by either binding or deacetylating PPARY [24-26]. In IWAT, we show an enrichment of proteins involved in retinol metabolism, a well-known pathway which drives both adipogenesis and lipogenesis which is dependent on an intact NAD+ binding motif [27].…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…Valproic acid, classified as a nonspecific HDAC inhibitor, along with trichostatin A and butyric acid, are commonly used in the management of mood disorders and epilepsy to promote visceral obesity in humans by increasing newly formed adipocytes, similar to corticosteroids. It has been shown that glucocorticoid receptor stimulates adipogenesis in part by enhancing the transcription of C/ebpa through the titration, and subsequent degradation, of HDAC1 from the C/ebpα promoter (Kuzmochka et al, 2014). Therefore, targeting HDAC1 (likely through activation) may serve as a possible avenue to prevent glucocorticoid-induced adiposity through regulation of CCAAT/enhancer-binding protein α (C/EBPα) levels in preadipocytes.…”

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

“…HDACs do not only modulate the acetylation of histones but also of non-histone proteins such as DNA binding transcription factors, steroid receptors, transcription coregulators and chaperone proteins (Glozak & Seto 2007). Recent data by Kuzmochka et al (2014) show that inactivation of HDAC1 promotes adipose conversion. However, other studies indicate that inhibitors of HDACs repress expression of the late markers of differentiation CEBPa (Catalioto et al 2009) and aP2 (Haberland et al 2010) and curb adipogenesis.…”