Cited by 605Adipose Tissue and MetabolismPeroxisome Proliferator-Activated ReceptorsMetabolism, Diabetes, and Cancer

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

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Cao, Wenhong, Daniel, Kiefer W., Robidoux, Jacques, Puigserver, Pere, Medvedev, Alexander V., Bai, Xu, Floering, Lisa M., Spiegelman, Bruce M., Collins, Sheila·2004·Molecular and Cellular Biology

DOI 10.1128/mcb.24.7.3057-3067.2004PMC PMC371122

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Abstract

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.

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A distal enhancer with ETV4 binding is critical for UCP1 expression and thermogenesis in brown fatPreprint
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Authors: Cao, W., Daniel, K. W., Robidoux, J., Puigserver, P., Medvedev, A. V., Bai, X., Floering, L. M., Spiegelman, B. M., & Collins, S.
Affiliations: Duke University (US)
Harvard University (US)
Corresponding author: Collins, Sheila
ORCID: Cao, Wenhong
Robidoux, Jacques
Puigserver, Pere
Medvedev, Alexander V.
Spiegelman, Bruce M.
Collins, Sheila
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2004-04-01
Volume: 24
Issue: 7
Pages: 3057-3067
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.24.7.3057-3067.2004
PMC: PMC371122
OpenAlex: W2162186867
Cited by: 605
References: 46
Citations by year: 2026: 17 · 2025: 33 · 2024: 36 · 2023: 29 · 2022: 28 · 2021: 46 · 2020: 51 · 2019: 28 · 2018: 29 · 2017: 29 · 2016: 37 · 2015: 27 · 2014: 26 · 2013: 34 · 2012: 26
FWCI: 10.31
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (DK54477)
National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-54024, R01 DK54477, R01DK054024, R01DK053092, R01DK054477)
Topics: Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: p38 MAPK, UCP1, brown adipocytes, thermogenesis, cAMP signaling, protein kinase A, ATF2, PGC-1α, PPAR response element, cAMP response element, enhancers, catecholamine signaling, beta-adrenergic signaling
MeSH terms: Uncoupling Protein 1, Cyclic AMP, Animals, Adipose Tissue, Brown, Carrier Proteins, Cells, Cultured, Cold Temperature, Enhancer Elements, Genetic, Enzyme Activation, Enzyme Inhibitors, Gene Expression Regulation, Humans, Ion Channels, Membrane Proteins, Mice, Inbred C57BL, Random Allocation, Transcription Factors, Transcription, Genetic, Uncoupling Agents, Signal Transduction, Adipocytes, Mitogen-Activated Protein Kinases, Thermogenesis, Mitochondrial Proteins, p38 Mitogen-Activated Protein Kinases, Mice

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

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