The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene
Open accessAbstract
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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“The most well-known condition to induce Ucp1 expression in both humans and rodents is cold, essentially by activating β-adrenergic receptors and the cAMP-dependent protein kinase (PKA)-dependent signaling pathway [38,39].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [39]
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Self-citationA Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis
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Self-citationEpac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP
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Items 601–604 of 604
Hu, B., Liu, Y., Zhang, X., & Manickam, S. (2026) · Nutrition Reviews · doi:10.1093/nutrit/nuag146
Orexin Signalling in Brown Adipose Tissue Precursor Cells
Hunter, K. (2013) · Työväentutkimus Vuosikirja
Role of caveolin-1 in brown adipose tissue
Mattsson, C. L. (2010) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Metadata
- 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
- 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
- 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
- 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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