Multiple Roles for Steroid Receptor RNA Activator (SRA) in Regulation of Adipogenesis and Insulin Sensitivity

PPAR is a master transcriptional regulator of adipogenesis. Hence, the identification of PPAR coactivators should help reveal mechanisms controlling gene expression in adipose tissue development and physiology. We show that the non-coding RNA Steroid receptor RNA Activator, SRA, associates with PPAR and coactivates PPAR-dependent reporter gene expression. Overexpression of SRA in ST2 adipocyte precursor cells promotes their differentiation into adipocytes. Conversely, knockdown of endogenous SRA inhibits 3T3-L1 preadipocyte differentiation. Microarray analysis reveals hundreds of SRA-responsive genes in adipocytes, including genes in cell cycle, insulin and TNF signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPAR. SRA increases insulin-stimulated glucose uptake in adipocytes. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of cyclin-dependent kinase inhibiters p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the TNF-induced phosphorylation of c-Jun NH2-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.

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