1 Genome Research and Molecular Bio Medicine, Department of Biology, Faculty of Science, Københavns Universitet2 Department of Biology, Faculty of Science, Københavns Universitet3 Institut for Biokemi og Molekylær Biologi4 Odense University Hospital5 Institut for Fødevarer - Fødevarer, Metabolomics og Sensorik6 Cell Biology and Physiology, Department of Biology, Faculty of Science, Københavns Universitet7 Genome Research and Molecular Bio Medicine, Department of Biology, Faculty of Science, Københavns Universitet8 Cell Biology and Physiology, Department of Biology, Faculty of Science, Københavns Universitet9 Department of Biology, Faculty of Science, Københavns Universitet
Adipocyte differentiation is orchestrated by the ligand-activated nuclear receptor PPAR. Endogenous ligands comprise oxidized derivatives of arachidonic acid and structurally similar PUFAs. Although expression of PPAR peaks in mature adipocytes, ligands are produced primarily at the onset of differentiation. Concomitant with agonist production, murine fibroblasts undergo two rounds of mitosis referred to as mitotic clonal expansion. Here we show that mouse embryonic fibroblasts deficient in either of two cell cycle inhibitors, the transcription factor p53 or its target gene encoding the cyclin-dependent kinase inhibitor p21, exhibit increased adipogenic potential. The antiadipogenic effect of p53 relied on its transcriptional activity and p21 expression but was circumvented by administration of an exogenous PPAR agonist suggesting a linkage between cell cycling and PPAR ligand production. Indeed, cell cycle inhibitory compounds decreased PPAR ligand production in differentiating 3T3-L1 preadipocytes. Furthermore, these inhibitors abolished the release of arachidonic acid induced by the hormonal cocktail initiating adipogenesis. Collectively, our results suggest that murine fibroblasts require clonal expansion for PPAR ligand production at the onset of adipocyte differentiation.
Journal of Lipid Research, 2014, Vol 55, Issue 12, p. 2491-2500