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PPAR Research
Volume 2013, Article ID 476049, 8 pages
http://dx.doi.org/10.1155/2013/476049
Research Article

Synergism between cAMP and PPAR Signalling in the Initiation of UCP1 Gene Expression in HIB1B Brown Adipocytes

School of Biosciences, Division of Nutritional Sciences, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicestershire LE125RD, UK

Received 18 October 2012; Revised 14 December 2012; Accepted 28 December 2012

Academic Editor: Richard P. Phipps

Copyright © 2013 H. Y. Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Expression of the brown adipocyte-specific gene, uncoupling protein 1 (UCP1), is increased by both PPAR stimulation and cAMP activation through their ability to stimulate the expression of the PPAR coactivator PGC1 . In HIB1B brown preadipocytes, combination of the PPAR agonist, rosiglitazone, and the cAMP stimulator forskolin synergistically increased UCP1 mRNA expression, but PGC1 expression was only increased additively by the two drugs. The PPAR antagonist, GW9662, and the PKA inhibitor, H89, both inhibited UCP1 expression stimulated by rosiglitazone and forskolin but PGC1 expression was not altered to the same extent. Reporter studies demonstrated that combined rosiglitazone and forskolin synergistically activated transcription from a full length 3.1 kbp UCP1 luciferase promoter construct, but the response was only additive and much reduced when a minimal 260 bp proximal UCP1 promoter was examined. Rosiglitazone and forskolin in combination were able to synergistically stimulate promoters comprising of tandem repeats of either PPREs or CREs. We conclude that rosiglitazone and forskolin act together to synergistically activate the UCP1 promoter directly rather than by increasing PGC1 expression and by a mechanism involving cross-talk between the signalling systems regulating the CRE and PPRE on the promoters.