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J. Biol. Chem., Vol. 282, Issue 29, 21005-21014, July 20, 2007

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Sequential Regulation of Diacylglycerol Acyltransferase 2 Expression by CAAT/Enhancer-binding Protein (C/EBP) and C/EBP during Adipogenesis^*

Victoria A. Payne, Wo-Shing Au, Sarah L. Gray, Edoardo Dalla Nora, Shaikh M. Rahman, Rebecca Sanders, Dirk Hadaschik, Jacob E. Friedman, Stephen O'Rahilly¹, and Justin J. Rochford¹²

From the Department of Clinical Biochemistry, University of Cambridge, Box 232, Level 4, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom and the Department of Pediatrics, University Colorado Health Sciences Center, Denver, Colorado 80262

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triacylglycerol (TG) synthesis. Despite the existence of an alternative acyltransferase (DGAT1), mice lacking DGAT2 have a severe deficiency of TG in adipose tissue, indicating a nonredundant role for this enzyme in adipocyte TG synthesis. We have studied the regulation of DGAT2 expression during adipogenesis. In both isolated murine preadipocytes and 3T3-L1 cells the temporal pattern of DGAT2 expression closely mimicked that of genes whose expression is regulated by CAAT/enhancer-binding protein (C/EBP). Inhibition of C/EBP expression in differentiating preadipocytes reduced DGAT2 expression, and electrophoretic mobility shift assay and chromatin immunoprecipitation experiments identified a promoter element in the DGAT2 gene that is likely to mediate this effect. The importance of C/EBP in adipocyte expression of DGAT2 was confirmed by the finding of reduced DGAT2 expression in the adipose tissue of C/EBP-null animals. However, DGAT2 expression is maintained at high levels during the later stages of adipogenesis, when C/EBP levels decline. We show that, at these later stages of differentiation, C/EBP is capable of substituting for C/EBP at the same promoter element. These observations provide novel insight into the transcriptional regulation of DGAT2 expression. Moreover, they further refine the complex and serial roles of the C/EBP family of transcription factors in inducing and maintaining the metabolic properties of mature adipocytes.

Received for publication, April 4, 2007 , and in revised form, May 1, 2007.

^* This work was supported in part by the British Heart Foundation (to J. J. R.), the Wellcome Trust (to V. A. P., D. H., and S. O. R.), The Dorothy Hodgkin Postgraduate Award Scheme (to W.-S. A.), the Natural Sciences and Engineering Research Council of Canada (to S. L. G.), the O. Arlotti Trust, Italy (to E. D. N.), and through National Institutes of Health Grant DK059767 (to J. E. F. and S. M. H.). 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 Members of the EUGENE2 Consortium.

² To whom correspondence should be addressed. Tel.: 44-1223-767-188; Fax: 44-1223-330-598; E-mail: jjr30{at}cam.ac.uk.

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