The Retinoblastoma-Histone Deacetylase 3 Complex Inhibits PPARγ and Adipocyte Differentiation

Fajas, Lluís; Egler, Viviane; Reiter, Raphael; Hansen, Jacob B.; Kristiansen, Karsten; Debril, Marie-Bernard; Miard, Stéphanie; Auwerx, Johan

doi:10.1016/s1534-5807(02)00360-x

Cited by 253 publications

(227 citation statements)

References 27 publications

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“…19 The role of the retinoblastoma protein family members, or the pocket proteins pRB, p130, and p107, in adipocyte differentiation is still controversial. The negative role of pocket proteins in cell cycle progression, repressing the expression of the E2F target genes, has been demonstrated in several settings.…”

Section: Regulation Of Pparc Activitymentioning

confidence: 99%

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Atypical transcriptional regulators and cofactors of PPARγ

Miard

Fajas

2005

Int J Obes

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Regulation of peroxisome proliferator-activated receptor gamma (PPARg) activity is the result of several events. The first control level is the regulation of the expression of PPARg. Examples of this regulation, during adipogenesis, is the transactivation of the PPARg promoter by transcription factors of the classical pathway, such as C/EBPs or ADD1/SREBP1, but also newly identified factors, such as E2Fs. When preadipocytes re-enter the cell cycle, PPARg expression is induced coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. E2F1 induces PPARg transcription during clonal expansion, whereas E2F4 represses PPARg expression during terminal adipocyte differentiation. Hence, E2Fs represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARg expression. A second regulatory level of PPARg action is interaction with cofactors. We will focus our attention on the atypical PPARg modulators. We have described an interaction between PPARg and the retinoblastoma protein, RB, which is both dependent upon ligand binding by PPARg and upon the phosphorylation status of RB. The interaction between PPARg and RB decreases the transcriptional activity of PPARg through recruitment of the histone deacetylase HDAC3. Inhibition of HDAC activity consequently results in a strong activation of PPARg.

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Section: Regulation Of Pparc Activitymentioning

confidence: 99%

“…Dissociation of the PPARg-RB-HDAC3 complex by RB phosphorylation or by inhibition of HDAC activity stimulates adipocyte differentiation. 19 Clearly, more in vivo studies, such as the ones utilizing adipose tissue-specific RB knockout mice, are required to elucidate the role of RB in adipogenesis.…”

Section: Regulation Of Pparc Activitymentioning

confidence: 99%

Atypical transcriptional regulators and cofactors of PPARγ

Miard

Fajas

2005

Int J Obes

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“…Notably, PPARg induces adipocyte differentiation more robustly in the absence of RB because formation of PPARg-RB-HDAC3 complexes represses the nuclear receptor's ability to drive gene expression and adipogenesis. 10 Conversely, dissociation of this receptorcofactor heterotrimer stimulates adipocyte differentiation.…”

mentioning

confidence: 99%

Role of PPARγ, transcriptional cofactors, and adiponectin in the regulation of nutrient metabolism, adipogenesis and insulin action: view from the chair

Berger

2005

Int J Obes

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The peroxisome proliferator-activated receptors (PPARs) compose a nuclear receptor subfamily. 1 The three PPAR isoforms, g, a and d, which are encoded by three separate genes, are nutrient sensors that regulate metabolic homeostasis. They are ligand-regulated transcription factors whose main physiological actions are mediated by altering gene expression. PPARs heterodimerize with RXR, then bind to peroxisome proliferator response elements in regulatory domains of genes. Upon being bound by agonists, PPAR conformation is changed such that it binds with high affinity to coactivators that remodel chromatin and communicate with the cellular transcriptional machinery. As a result, transcriptional initiation is induced and the levels of PPAR-responsive transcripts increase.PPARg is highly expressed in adipose tissue. Activation of PPARg induces adipocyte differentiation and lipid accumulation by adipocytes by modulating numerous genes regulating adipogenesis, lipid uptake and lipid metabolism. Notably, PPARg null cells cannot differentiate into adipocytes and the adipose-specific ablation of PPARg results in adipocyte hypocellularity and reduced adiposity. Thiazolidinedione (TZD) insulin-sensitizing agents are PPARg ligands; their antidiabetic efficacy in vivo has been shown to correlate with their receptor agonist potency. The insulin-sensitizing action of PPARg agonists results from their ability to lower circulating free fatty acids by decreasing adipocyte lipolysis, regulate the expression of proteins that modulate insulin action and serve as adipose remodeling agents that direct lipids away from lipolytic visceral fat depots and into subcutaneous fat tissue containing small, insulin-responsive adipocytes. 2 PPARg coactivator-1 (PGC-1), a transcriptional coactivator that was first identified as a result of its high affinity for the receptor from which it takes its name, was discussed by Pere Puigserver. Only by interacting with PGC-1 and activating the transcription of mitochondrial UCP-1 can PPARg induce brown adipocyte differentiation. 3 To induce the expression of all the genes required for a complete thermogenic response in brown adipocytes, PGC-1 also serves as a coactivator of other nuclear receptors including PPARa, TR, RAR and ERRa. Additionally, when thermogenesis is required, PGC-1 is upregulated and stabilized by the sympathetic nervous system via activation of b-adrenoreceptor transduction pathways.PGC-1 also plays a critical role in the differentiation and metabolic activity of skeletal muscle, a major site of energy utilization during exercise. 4 The coactivator is sufficient for the induction of mitochondria biogenesis and the generation of type 1 (slow twitch) muscle. Calcium signaling cascades elevate PGC-1 muscle expression by activating transcription factors that have response elements in the coactivator's promoter. Pharmacological activation of PGC-1 in muscle might mitigate obesity.PGC-1 not only induces lipid catabolism but also hepatic gluconeogenesis during the fasted and diabetic states. 5...

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“…27, mai 2011 ment du tissu adipeux est controversé : certaines études suggèrent que pRb favoriserait l'adipogenèse [10][11][12], d'autres au contraire qu'elle l'inhiberait, via son interaction avec PPAR et HDAC3 (histone déacétylase 3) sur des promoteurs cibles de PPAR, inhibant ainsi le processus adipogénique [13]. Des rôles opposés de Rb dans les différentes phases de l'adipogenèse sont donc possibles.…”

Section: Revuesunclassified

Le double jeu des régulateurs du cycle cellulaire

et al. 2011

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> Depuis la découverte des cyclines, de nombreuses études illustrent le rôle émergent des régulateurs du cycle cellulaire dans différentes fonctions métaboliques telles que l'adipogenèse, l'homéostasie glucidique et la dépense énergé-tique. L'étude de différents modèles murins, au travers de l'invalidation d'acteurs du cycle cellulaire tels que des cyclines (Cyc) ou des kinases dépendantes des cyclines (Cdk), ou celle de facteurs de transcription, a permis de mettre à jour leur rôle prépondérant dans ces différentes voies métaboliques. Dans cette revue, nous explorerons les différents rôles des régulateurs du cycle cellulaire, indépendamment de leur contrôle sur la prolifération. < En plus de leur rôle dans la régulation de la prolifération, et indé-pendamment, les acteurs du cycle cellulaire influencent le contrôle du métabolisme. En effet, ils sont capables de mettre en place une réponse métabolique adaptée en fonction du statut de la cellule.Les acteurs du cycle cellulaire dans la différenciation adipocytaire Les deux phases du processus de différenciation adipocytaire Le tissu adipeux blanc est l'organe essentiel de stockage d'énergie dans le corps, son principal rôle étant de fournir de l'énergie, via les lipides, aux autres tissus en cas de nécessité. Cette fonction est assurée par le processus de lipolyse qui consiste en la dégradation des triglycérides (TG) en glycérol et acides gras libres (FFA pour free fatty acids) [4]. À l'inverse, le tissu adipeux blanc a également un rôle de synthèse et de stockage des acides gras. L'étude du dévelop-pement du tissu adipeux est très pertinente comme modèle d'étude de l'implication des acteurs du cycle cellulaire dans le métabolisme puisqu'il met en jeu à la fois la prolifération et la différenciation. En effet, le mécanisme d'adipogenèse correspond à la succession de deux événements majeurs : la prolifération de précurseurs (préadi-pocytes) et leur différenciation en adipocytes matures (Figure 2). Une relation étroite a été établie entre ces deux processus cellulaires au cours du programme de différenciation adipocytaire [5]. Les étu-des in vivo entreprises afin de déterminer les mécanismes molécu-laires au cours de l'adipogenèse étant limitées, des modèles in vitro utilisant des lignées préadipocytaires de cellules murines 3T3-L1 ont

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The Retinoblastoma-Histone Deacetylase 3 Complex Inhibits PPARγ and Adipocyte Differentiation

Cited by 253 publications

References 27 publications

Atypical transcriptional regulators and cofactors of PPARγ

Atypical transcriptional regulators and cofactors of PPARγ

Role of PPARγ, transcriptional cofactors, and adiponectin in the regulation of nutrient metabolism, adipogenesis and insulin action: view from the chair

Le double jeu des régulateurs du cycle cellulaire

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