Multiple roles for the non-coding RNA SRA in regulation of adipogenesis and insulin sensitivity.

ABSTRACT: Peroxisome proliferator-activated receptor-? (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 mesenchymal 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 involved in the cell cycle, and insulin and TNF? signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPAR?. SRA in adipocytes increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the expression of adipocyte-related inflammatory genes and TNF?-induced phosphorylation of c-Jun NH(2)-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.

SUBMITTER: Xu B 

PROVIDER: S-EPMC2996286 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature