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Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation
Open accessAbstract
Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and brown adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. brown adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo fibroblasts (MEFs) and white preadipocytes by expression of simian virus 40 large T antigen results in the expression of the brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient ( Rb – / – ) MEFs and stem cells, but not the corresponding wild-type cells, differentiate into adipocytes with a gene expression pattern and mitochondria content resembling brown adipose tissue. pRB-deficient MEFs exhibit an increased expression of the Forkhead transcription factor Foxc2 and its target gene cAMP-dependent protein kinase regulatory subunit RIα, resulting in increased cAMP sensitivity. Suppression of cAMP-dependent protein kinase activity in Rb –/– MEFs blocked the brown adipocyte-like gene expression pattern without affecting differentiation per se . Immunohistochemical studies revealed that pRB is present in the nuclei of white but not brown adipocyte precursor cells at a developmental stage where both cell types begin to accumulate lipid and brown adipocytes express UCP-1. Furthermore, pRB rapidly undergoes phosphorylation upon cold-induced neodifferentiation and up-regulation of UCP-1 expression in brown adipose tissue. Finally, down-regulation of pRB expression accompanies transdifferentiation of white into brown adipocytes in response to β3-adrenergic receptor agonist treatment. We propose that pRB acts as a molecular switch determining white vs. brown adipogenesis, suggesting a previously uncharacterized function of this key cell cycle regulator in adipocyte lineage commitment and differentiation.
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“Among the known inhibitors of preadipocyte-adipocyte transition, proteins of the retinoblastoma (Rb) family, and necdin, a growth repressor functionally resembling Rb, selectively inhibit brown preadipocyte differentiation 132,133,168”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [132]
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Metadata
- Authors
- Hansen, J. B., Jørgensen, C., Petersen, R. K., Hallenborg, P., De Matteis, R., Bøye, H. A., Petrovic, N., Enerbäck, S., Nedergaard, J., Cinti, S., Riele, H. T., & Kristiansen, K.
- Affiliations
- Stockholm University (SE)
- Departments of Biochemistry and Molecular Biology and Anatomy and Neurobiology, University of Southern Denmark, DK-5230 Odense M, Denmark; The Netherlands Cancer Institute, Division of Molecular Biology, NL-1066 CX Amsterdam, The Netherlands; Institute of Normal Human Morphology, Faculty of Medicine, University of Ancona, Ancona 60020, Italy; The Wenner-Gren Institute, Stockholm University, SE-10691 Stockholm, Sweden; and Medical Genetics, Department of Medical Biochemistry, Göteborg University, SE...
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-03-15
- Volume
- 101
- Issue
- 12
- Pages
- 4112-4117
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC384703
- OpenAlex
- W2145157621
- Cited by
- 287
- References
- 36
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 15 · 2017: 12 · 2016: 11 · 2015: 14 · 2014: 16 · 2013: 23 · 2012: 23
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Update notices
- correction (2004-04-27)
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- 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
- retinoblastoma protein, white adipocyte differentiation, brown adipocyte differentiation, UCP1, FOXC2, protein kinase A, protein phosphorylation, beta3-adrenergic agonists, adipocyte transdifferentiation, adipose tissue
- MeSH terms
- Uncoupling Protein 1, Cyclic AMP, Animals, Antigens, Polyomavirus Transforming, Adipose Tissue, Brown, Carrier Proteins, Cell Differentiation, Fibroblasts, Ion Channels, Membrane Proteins, Mice, Inbred C57BL, Simian virus 40, Retinoblastoma Protein, Rats, Sprague-Dawley, Adipocytes, Mitochondrial Proteins, Mice, Rats
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