TY - JOUR
T1 - p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene
AU - Cao, Wenhong
AU - Daniel, Kiefer W.
AU - Robidoux, Jacques
AU - Puigserver, Pere
AU - Medvedev, Alexander V.
AU - Bai, Xu
AU - Floering, Lisa M.
AU - Spiegelman, Bruce M.
AU - Collins, Sheila
PY - 2004/4
Y1 - 2004/4
N2 - It is well established that catecholamine-stimulated thermogenesis in brown fat requires β-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-γ) coativator 1α (PGC-1α), 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-1α 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.
AB - It is well established that catecholamine-stimulated thermogenesis in brown fat requires β-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-γ) coativator 1α (PGC-1α), 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-1α 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.
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U2 - 10.1128/MCB.24.7.3057-3067.2004
DO - 10.1128/MCB.24.7.3057-3067.2004
M3 - Article
C2 - 15024092
AN - SCOPUS:1642293248
SN - 0270-7306
VL - 24
SP - 3057
EP - 3067
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 7
ER -