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J. Biol. Chem., Vol. 279, Issue 22, 22803-22808, May 28, 2004

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A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes^*

Luke A. Noon, Adrian J. L. Clark, and Peter J. King

From the Molecular Endocrinology Center, William Harvey Research Institute, Bart's and the London, Queen Mary University of London, London, EC1A 7BE, United Kingdom

Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5' deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocyte-specific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor (PPAR) and its heterodimeric partner retinoid X receptor (RXR) in adipocyte nuclear extracts. Co-transfection of PPAR2/RXR with the pMC2-R(–112/+105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPAR/RXR binding resulted in a complete abrogation of the pMC2-R(–112/+105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.

Received for publication, February 20, 2004

^* This work was funded by the Joint Research Board of St. Bartholomew's Hospital (London, United Kingdom). 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.

To whom correspondence should be addressed. Tel.: 44-20-7601-7444; Fax: 44-20-7601-8468; E-mail: p.j.king{at}qmul.ac.uk.

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