p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.

Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, Floering LM, Spiegelman BM, Collins S
Mol Cell Biol. 2004 24 (7): 3057-67

PMID: 15024092 · PMCID: PMC371122 · DOI:10.1128/mcb.24.7.3057-3067.2004

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.

MeSH Terms (26)

Adipocytes Adipose Tissue, Brown Animals Carrier Proteins Cells, Cultured Cold Temperature Cyclic AMP Enhancer Elements, Genetic Enzyme Activation Enzyme Inhibitors Gene Expression Regulation Humans Ion Channels Membrane Proteins Mice Mice, Inbred C57BL Mitochondrial Proteins Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases Random Allocation Signal Transduction Thermogenesis Transcription, Genetic Transcription Factors Uncoupling Agents Uncoupling Protein 1

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