title: Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation.
abstract: 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 RIalpha, 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 beta3-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Hansen
authors.forename: Claus
authors.initials: C
authors.lastname: Jørgensen
authors.forename: Rasmus K
authors.initials: RK
authors.lastname: Petersen
authors.forename: Philip
authors.initials: P
authors.lastname: Hallenborg
authors.forename: Rita
authors.initials: R
authors.lastname: De Matteis
authors.forename: Hans A
authors.initials: HA
authors.lastname: Bøye
authors.forename: Natasa
authors.initials: N
authors.lastname: Petrovic
authors.forename: Sven
authors.initials: S
authors.lastname: Enerbäck
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.forename: Hein
authors.initials: H
authors.lastname: te Riele
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000502:physiology*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D005347:Fibroblasts; D007473:Ion Channels; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013539:Simian virus 40 / Q000502:physiology; D000071256:Uncoupling Protein 1
chemical_list: D000952:Antigens, Polyomavirus Transforming; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016160:Retinoblastoma Protein; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D000242:Cyclic AMP