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Molecular and Cellular Biology, November 2005, p. 9985-9995, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.9985-9995.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Cyclin D3 Promotes Adipogenesis through Activation of Peroxisome Proliferator-Activated Receptor {gamma}

David A. Sarruf,1 Irena Iankova,1,{dagger} Anna Abella,1,{dagger} Said Assou,1 Stéphanie Miard,1 and Lluis Fajas1,2*

INSERM, Equipe Avenir, U540, F34090 Montpellier, France,1 Centre Hostpitalier Universitaire Montpellier, F34295 Montpellier, France2

Received 15 February 2005/ Returned for modification 8 April 2005/ Accepted 7 August 2005

In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}). Our experiments reveal cyclin D3 acts as a ligand-dependent PPAR{gamma} coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPAR{gamma} activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPAR{gamma} target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.

* Corresponding author. Mailing address: INSERM, U540 Equipe Avenir, 60, rue de Navacelles. 34090 Montpellier, France. Phone: 33(0)4 67 04 30 82. Fax: 33 (0)4 67 54 05 98. E-mail: fajas{at}montp.inserm.fr.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2005, p. 9985-9995, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.9985-9995.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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