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Molecular and Cellular Biology, April 2004, p. 3057-3067, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.3057-3067.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene

Wenhong Cao,1 Kiefer W. Daniel,1 Jacques Robidoux,1 Pere Puigserver,2 Alexander V. Medvedev,1 Xu Bai,1 Lisa M. Floering,1 Bruce M. Spiegelman,2 and Sheila Collins1*

Departments of Psychiatry and Behavioral Sciences and Pharmacology, Duke University Medical Center, Durham, North Carolina 27710,1 Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021152

Received 22 October 2003/ Returned for modification 4 December 2003/ Accepted 5 January 2004

It is well established that catecholamine-stimulated thermogenesis in brown fat requires ß-adrenergic elevations in cyclic AMP (cAMP) to increase expression of the uncoupling protein 1 (UCP1) gene. However, little is known about the downstream components of the signaling cascade or the relevant transcription factor targets thereof. Here we demonstrate that cAMP- and protein kinase A-dependent activation of p38 mitogen-activated protein kinase (MAPK) in brown adipocytes is an indispensable step in the transcription of the UCP1 gene in mice. By phosphorylating activating transcription factor 2 (ATF-2) and peroxisome proliferator-activated receptor gamma (PPAR{gamma}) coativator 1{alpha} (PGC-1{alpha}), members of two distinct nuclear factor families, p38 MAPK controls the expression of the UCP1 gene through their respective interactions with a cAMP response element and a PPAR response element that both reside within a critical enhancer motif of the UCP1 gene. Activation of ATF-2 by p38 MAPK additionally serves as the cAMP sensor that increases expression of the PGC-1{alpha} gene itself in brown adipose tissue. In conclusion, our findings illustrate that by orchestrating the activity of multiple transcription factors, p38 MAPK is a central mediator of the cAMP signaling mechanism of brown fat that promotes thermogenesis.

* Corresponding author. Present address: CIIT Centers for Health Research, 6 Davis Dr., P.O. Box 12137, Research Triangle Park, NC 27709-2137. E-mail: scollins{at}ciit.org.

Molecular and Cellular Biology, April 2004, p. 3057-3067, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.3057-3067.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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