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Transforming Growth Factor-β Inhibits Adipocyte Differentiation by Smad3 Interacting with CCAAT/Enhancer-binding Protein (C/EBP) and Repressing C/EBP Transactivation Function
Open accessAbstract
Transforming growth factor (TGF)-beta is a potent inhibitor of adipocyte differentiation. To identify which adipocyte transcription factors might be targeted by TGF-beta, we overexpressed key adipogenic transcription factors, C/EBPbeta, C/EBPdelta, or peroxisome proliferator-activated receptor (PPAR) gamma in NIH3T3 cells and tested the ability of TGF-beta to block adipogenesis. We show that TGF-beta inhibits adipocyte differentiation driven by either C/EBPbeta or C/EBPdelta without affecting C/EBP protein expression levels, suggesting that these C/EBPs are a direct target of TGF-beta action. Because TGF-beta inhibits adipogenesis by signaling through Smad3, we examined physical and functional interactions of Smad3 and Smad4 with C/EBPbeta, C/EBPdelta, and PPARgamma2. C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPARgamma2 and leptin promoters. In contrast, PPARgamma interacted only very weakly with Smad3 and its transcriptional activity was not repressed by Smad3/4 or in response to TGF-beta. Smad3/4 did not reduce the ability of C/EBP to bind to its cognate DNA sequence, but repressed transcription by inhibiting the transactivation function of C/EBP.
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“While TGF-β inhibits adipocyte differentiation in vitro 97 and TGF-β expression in fat is paradoxically increased with obesity in rodents and humans 98,99.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [97]
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Metadata
- Authors
- Choy, L., & Derynck, R.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Derynck, Rik
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 278
- Issue
- 11
- Pages
- 9609-9619
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2017292651
- Cited by
- 343
- References
- 64
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 9 · 2023: 14 · 2022: 13 · 2021: 19 · 2020: 19 · 2019: 18 · 2018: 21 · 2017: 21 · 2016: 13 · 2015: 21 · 2014: 10 · 2013: 27 · 2012: 21
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1k01dk002877-01)
- National Cancer Institute (R01CA063101, R01-CA63101)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01 DK02877)
- National Institute of Dental and Craniofacial Research (P60DE013058, P60 DE-13058)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- TGF-beta, adipogenesis, Smad3, SMAD4, C/EBPβ, C/EBPδ, PPARγ, transcriptional repression, protein-protein interaction, TGF-beta signaling
- MeSH terms
- Animals, Binding Sites, Cell Differentiation, Cell Line, DNA-Binding Proteins, Glutathione Transferase, Oligonucleotides, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, RNA, Transcription Factors, Transcription, Genetic, Transfection, Transcriptional Activation, Trans-Activators, Transforming Growth Factor beta, 3T3 Cells, Protein Structure, Tertiary, Adipocytes, Receptors, Cytoplasmic and Nuclear, Biotinylation, Leptin, CCAAT-Enhancer-Binding Proteins, CCAAT-Enhancer-Binding Protein-beta, Lipid Metabolism, Mice, CCAAT-Enhancer-Binding Protein-delta, Smad3 Protein, Smad4 Protein
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