Tudor-SN, a Novel Coactivator of Peroxisome Proliferatoractivated Receptor γ Protein, Is Essential for Adipogenesis

Background: Tudor-SN has been observed in lipid droplets, but its role in lipid homeostasis remains unclear. Results: Tudor-SN and PPAR are both regulated by C/EBP during adipogenesis and significantly influence the regulation of PPAR target genes. Conclusion: Tudor-SN functions as a co-activator of PPAR in adipogenesis. Significance: The study has elucidated a new functional mechanism for the regulation of adipogenesis. Adipogenesis, in which mesenchymal precursor cells differentiate into mature adipocytes, is a well orchestrated process. In the present study we identified Tudor-SN as a novel co-activator of the transcription factor peroxisome proliferator-activated receptor (PPAR). We provide the first evidence that Tudor-SN and PPAR exist in the same complex. Both are up-regulated by the early factor C/EBP during adipogenesis and significantly influence the regulation of PPAR target genes in both 3T3-L1 pre-adipocyte and mouse embryonic fibroblasts (MEF) upon exposure to a mixture of hormonal mixture. Moreover, aP2-PPAR response element (PPRE) interacts with both PPAR and Tudor-SN, and the gene transcriptional activation of PPRE-luc is enhanced by ectopic expression of Tudor-SN. Deletion of Tudor-SN protein (MEF-KO) affects but does not completely abolish the association of PPAR and aP2-PPRE. Loss-of-function studies further verified that Tudor-SN is required for adipogenesis, as deletion of Tudor-SN (MEF-KO) impairs dexamethasone, 3-isobutyl-1-methylxanthine, and insulin (DMI)-induced adipocyte differentiation and the expression of PPAR target genes, such as aP2 and adipsin. Furthermore, H3 acetylation levels were lower in MEF-KO than MEF-WT. Both HDAC1 and HDAC3 are stably associated with PPAR in MEF-KO, whereas only a small amount of association was observed in MEF-WT after 5 days of treatment during adipogenesis. PPAR requires various co-activators or co-repressors, which may dynamically associate with and regulate the higher order chromatin remodeling of the promoter region of PPAR-bound target genes; Tudor-SN is likely one of these co-activators.