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Abstract
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 γ (PPARγ). Our experiments reveal cyclin D3 acts as a ligand-dependent PPARγ 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 PPARγ activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPARγ 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.
ACKNOWLEDGMENTS
Jacques Teyssier is acknowledged for his technical assistance. We thank P. Sicinski for providing the cyclin D3 knockout mice and E. Sicinska and J. S. Annicotte for their helpful support and discussion.
This work was supported by grants from INSERM (Avenir), FRM, Alfediam, and ARC. Anna Abella is supported by an Inserm Poste Vert grant, and Irena Iankova is supported by La Ligue National Contre le Cancer Ph.D. fellowship. David Sarruf is supported by the Boehringer Ingelheim Fonds Ph.D. scholarship program.