Abstract
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Proceedings of the National Academy of Science of the United States of America |
| Vol/bind | 101 |
| Udgave nummer | 12 |
| Sider (fra-til) | 4112-4117 |
| ISSN | 0027-8424 |
| DOI | |
| Status | Udgivet - 2004 |
| Udgivet eksternt | Ja |
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I: Proceedings of the National Academy of Science of the United States of America, Bind 101, Nr. 12, 2004, s. 4112-4117.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
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TY - JOUR
T1 - Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation
AU - Hansen, Jacob B.
AU - Jørgensen, Claus
AU - Petersen, Rasmus K.
AU - Hallenborg, Philip
AU - Matteis, Rita De
AU - Bøye, Hans A.
AU - Petrovic, Natasa
AU - Enerbäck, Sven
AU - Nedergaard, Jan
AU - Cinti, Saverio
AU - Riele, Hein te
AU - Kristiansen, Karsten
PY - 2004
Y1 - 2004
N2 - 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 RIa, 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 ß3-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.
AB - 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 RIa, 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 ß3-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.
U2 - 10.1073/pnas.0301964101
DO - 10.1073/pnas.0301964101
M3 - Journal article
C2 - 15024128
SN - 0027-8424
VL - 101
SP - 4112
EP - 4117
JO - Proceedings of the National Academy of Science of the United States of America
JF - Proceedings of the National Academy of Science of the United States of America
IS - 12
ER -