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J. Biol. Chem., Vol. 282, Issue 34, 24660-24669, August 24, 2007

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C/EBP Reprograms White 3T3-L1 Preadipocytes to a Brown Adipocyte Pattern of Gene Expression^*

Georgios Karamanlidis, Angeliki Karamitri^¶, Kevin Docherty^¶, David G. Hazlerigg, and Michael A. Lomax^¶1

From the School of Biological Sciences, University of Aberdeen, Aberdeen, AB24 5UH, United Kingdom, Division of Biomedical Science, Imperial College, Wye Campus, Ashford, Kent TN25 5AH, United Kingdom, and ^¶Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom

cAMP-dependent protein kinase induction of PPAR coactivator-1 (PGC-1) and uncoupling protein 1 (UCP1) expression is an essential step in the commitment of preadipocytes to the brown adipose tissue (BAT) lineage. We studied the molecular mechanisms responsible for differential expression of PGC-1 in HIB1B (BAT) and 3T3-L1 white adipose tissue (WAT) precursor cell lines. In HIB1B cells PGC-1 and UCP1 expression is cAMP-inducible, but in 3T3-L1 cells, expression is reduced and is cAMP-insensitive. A proximal 264-bp PGC-1 reporter construct was cAMP-inducible only in HIB1B cells and was suppressed by site-directed mutagenesis of the proximal cAMP response element (CRE). In electrophoretic mobility shift assays, the transcription factors CREB and C/EBP, but not C/EBP and C/EBP, bound to the CRE on the PGC-1 promoter region in HIB1B and 3T3-L1 cells. Chromatin immunoprecipitation studies demonstrated that C/EBP and CREB bound to the CRE region in HIB1B and 3T3-L1 cell lysates. C/EBP expression was induced by cAMP only in HIB1B cells, and overexpression of C/EBP rescued cAMP-inducible PGC-1 and UCP1 expression in 3T3-L1 cells. These data demonstrate that differentiation of preadipocytes toward the BAT rather than the WAT phenotype is controlled in part by the action of C/EBP on the CRE in PGC-1 proximal promoter.

Received for publication, April 12, 2007

^* This work was supported by the Biotechnology and Biological Sciences Research Council and the Greek State Scholarship's Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Inst. of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom. Tel.: 44-1224555844; Fax: 44-1224555844; E-mail: m.lomax{at}abdn.ac.uk.

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