Histone Deacetylase 9 Is a Negative Regulator of Adipogenic Differentiation

Department of Internal Medicine, Division of Cardiovascular Diseases, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2011; 286(31):27836-47. DOI: 10.1074/jbc.M111.262964
Source: PubMed


Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal deacetylase domain is dispensable for this function. HDAC9 co-precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBPα gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBPα promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBPα expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a deacetylase-independent mechanism.

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Available from: Neal Weintraub, Mar 12, 2014
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    • "Isoforms of the HDAC family are implicated in regulating lipid metabolism during adipogenesis (Iyer et al., 2012). Genetic deletion of Hdac1 and Hdac2 in mesenchymal precursor cells results in reduced adipogenesis and adipocyte differentiation, (Haberland et al., 2010), while Hdac9 knockout mice exhibited accelerated adipogenic differentiation (Chatterjee et al., 2011). Protein demethylase KDM3A is coupled to the regulation of genes involved in beta-adrenergic stimulated glycerol release and fatty acid oxidation such as uncoupling protein 1 (UCP1) (Tateishi et al., 2009). "
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    • "The role of histone acetylation on adipogenesis seems to be inconsistent; inhibition of HDAC activity by TSA inhibited adipogenesis in 3 T3-L1 cells [22], while it failed to inhibit adipogenesis in primary adipogenic precursor cells in mice and humans [28]. One thing we confirmed was that TSA-sensitive HDAC activity is not required for adipogenesis at least in hASCs ([28], our data Fig. 2D, E). Thus, the down-regulation of the TSA-insensitive portion of HDAC activity might be critical to initiate adipogenic differentiation. "
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    • "In the context of obesity, HDAC4 was also recently reported to be involved in regulation of GLUT4 during adipocyte differentiation [54] as well as promoting lypolysis [55]. Likewise, preadipocytes from HDAC9 KO mice exhibited accelerated adipogenic differentiation and thus, demonstrating its direct role as a negative regulator of adipogenesis [56]. The ubiquitin-binding HDAC6 was reported to play a crucial role in protein homeostasis “proteostasis” following accumulation of misfolded and aggregated proteins [57]. "
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