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 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.

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

“…Mechanisms of intracellular signaling sensitive to enhanced oxidative stress and altered energy metabolism (AMP-kinase, Sirt1, CHOP-10 and others) may convey these alterations into changes in overall adipocyte function and gene expression thus leading to impaired adipocyte differentiation, altered release of regulatory adipokines and enhanced apoptosis. 46 Acquisition of this proliferative status in association with some brown fat-like features is consistent with observations that inhibition of the activity of the retinoblastoma protein, a repressor of cell proliferation, drives pre-adipocytes to a brown versus a white phenotype 47 and may be associated with some intrinsic properties of brown adipocyte precursors to proliferate under physiopathological stimuli. In fact, brown adipose tissue in rodents is characterized by a capacity for dramatic enlargement, including cell proliferation, in response to external signals associated with thermogenic requirements.…”

Reversible physiological transdifferentiation in the adipose organ

“…Thus, the sympathetic nervous system seems to play a fundamental role in the plasticity of the adipose organ and a positive correlation has recently been shown between the density of noradrenergic parenchymal fibres and the density of brown adipocytes in the adipose organ under different environmental temperatures (15) . Figure 6 summarizes the morphological and immunohistochemistry stages of the physiological and reversible transdifferentiation of white into brown adipocytes, which is supported by data from a number of different research groups (48)(49)(50)(51)(52)(53)(54) .…”

JDP2 suppresses adipocyte differentiation by regulating histone acetylation

“…26 In addition to C/EBPs, as shown in the present studies, JDP2 might be a target of such signal networks. Other report suggested that the absence of retinoblastoma protein (Rb) switched the differentiation of MEF cells from white to brown adipocytes, 27 suggesting that the differentiation of WT MEFs to adipocytes is a good model for white adipocyte differentiation but not brown adipocyte differentiation. We also observed that PGC-1a, a marker of brown adipocyte, was not induced after induction of adipocyte differentiation in Jdp2 À/À MEFs and WT MEFs (data not shown).…”