View the Current Issue

Article

  • The EMBO Journal (2003) 22, 2135 - 2145
  • doi:10.1093/emboj/cdg218

Stimulation of preadipocyte differentiation by steroid through targeting of an HDAC1 complex

Nadine Wiper-Bergeron1,2, Dongmei Wu1, Louise Pope1, Caroline Schild-Poulter1 and Robert J.G. Haché1,2

  1. The Ottawa Health Research Institute, University of Ottawa, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9
  2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9

Correspondence to:

Robert J.G. Haché, E-mail: rhache@ohri.ca

Received 23 February 2003; Accepted 13 March 2003; Revised 11 March 2003

Glucocorticoids potentiate the early steps of preadipocyte differentiation and promote obesity in Cushing's syndrome and during prolonged steroid therapy. We show that glucocorticoids stimulate 3T3 L1 preadipocyte differentiation through a non-transcriptional mechanism mediated through the ligand-binding domain of the glucocorticoid receptor. This enhanced the onset of CCAAT/enhancer binding protein (C/EBPalpha) expression by potentiating its initial transcriptional activation by C/EBPbeta. In the absence of steroid, C/EBPbeta associated with a transcriptional corepressor complex containing mSin3A and histone deacetylase 1 (HDAC1), but lacking HDAC2 and RbAp46/48. HDAC1/mSin3A were recruited to the C/EBPalpha promoter with C/EBPbeta and promoted the deacetylation of histone H4. Steroid induced the specific depletion of this corepressor by targeting the HDAC1 within the complex for degradation through the 26S proteasome. Treatment with histone deacetylase inhibitors replaced the effects of steroid treatment on preadipocyte differentiation and C/EBPalpha expression, while overexpression of HDAC1 abrogated the stimulatory effects of steroid. Recapitulation of the glucocorticoid effect by progestin treatment in the presence of the progesterone receptor ligand-binding domain suggests a conserved mechanism relevant to many aspects of steroid-mediated differentiation.

  • Keywords:

    • CAAT enhancer binding protein beta function,
    • histone deacetylase 1,
    • initiation of preadipocyte differentiation,
    • 26S proteasome,
    • steroid hormone action