p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.
It is well established that catecholamine-stimulated thermogenesis in brown fat requires beta-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 (PPARgamma) coativator 1alpha (PGC-1alpha), 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-1alpha 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.
Cao
Wenhong
W
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA.
Daniel
Kiefer W
KW
Robidoux
Jacques
J
Puigserver
Pere
P
Medvedev
Alexander V
AV
Bai
Xu
X
Floering
Lisa M
LM
Spiegelman
Bruce M
BM
Collins
Sheila
S
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003080:Cold Temperature; D000242:Cyclic AMP / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011897:Random Allocation; D015398:Signal Transduction / Q000502:physiology; D022722:Thermogenesis / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D048051:p38 Mitogen-Activated Protein Kinases
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases