Retinoblastoma Protein Functions as a Molecular Switch Determining White versus Brown Adipocyte Differentiation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 12; pp. 4112 - 4117
• Main Authors: Hansen, Jacob B., Jørgensen, Claus, Petersen, Rasmus K., Hallenborg, Philip, De Matteis, Rita, Bøye, Hans A., Petrovic, Natasa, Enerbäck, Sven, Nedergaard, Jan, Cinti, Saverio, Riele, Hein te, Kristiansen, Karsten, Spiegelman, Bruce M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23-03-2004; National Acad Sciences
• Subjects: Adipocytes; Adipocytes - physiology; Adipose Tissue; Adipose Tissue, Brown - physiology; Animals; Antigens; Antigens, Polyomavirus Transforming - physiology; Biological Sciences; biosynthesis; Brown; Brown adipocytes; Brown adipose tissue; Carrier Proteins; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Cell Differentiation; Cell Differentiation - physiology; Cell lines; Cellular biology; Cellular differentiation; Cyclic AMP; Cyclic AMP - physiology; deficiency; Embryonic stem cells; Fibroblasts; Gene expression; genetics; Inbred C57BL; Ion Channels; MEDICAL AND HEALTH SCIENCES; MEDICIN OCH HÄLSOVETENSKAP; Membrane Proteins; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Messenger RNA; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; physiology; Polyomavirus Transforming; Proteins; Rats; Rats, Sprague-Dawley; Retinoblastoma Protein; Retinoblastoma Protein - deficiency; Retinoblastoma Protein - genetics; Retinoblastoma Protein - physiology; Reverse transcriptase polymerase chain reaction; Simian virus 40; Simian virus 40 - physiology; Sprague-Dawley; Stem cells; Uncoupling Protein 1; White adipocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0301964101

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 genedeficient (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.