title: 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.
authors.affiliation: Northern Ontario School of Medicine, Ontario, Canada ON POM Reproduction, Mother and Youth Health (H.-S.A.), CHUQ Research Centre, Quebec city, Quebec, Canada G1R2J6; Environmental Health Science and Research Bureau (E.A.), Health Canada, Ottawa, Ontario, Canada M3J1P3; and York University (R.J.G.H.), Toronto, Ontario, Canada K1A0K9.
authors.forename: Claire
authors.initials: C
authors.lastname: Kuzmochka
authors.forename: Houssein-Salem
authors.initials: HS
authors.lastname: Abdou
authors.forename: Robert J G
authors.initials: RJ
authors.lastname: Haché
authors.forename: Ella
authors.initials: E
authors.lastname: Atlas
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003907:Dexamethasone; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009765:Obesity / Q000139:chemically induced*; D047495:PPAR gamma / Q000378:metabolism; D034741:RNA, Small Interfering
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D056572:Histone Deacetylase Inhibitors; D047495:PPAR gamma; D034741:RNA, Small Interfering; D003907:Dexamethasone; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2