Multiple Roles for the Non-Coding RNA SRA in Regulation of Adipogenesis and Insulin Sensitivity

Bin Xu*, Isabelle Gerin, Hongzhi Miao, [No Value] Dang Vu-Phan, Craig N. Johnson, Ruichuan Xu, Xiao-Wei Chen, William P. Cawthorn, Ormond A. MacDougald, Ronald J. Koenig

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a master transcriptional regulator of adipogenesis. Hence, the identification of PPAR gamma 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 gamma and coactivates PPAR gamma-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 alpha signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPAR gamma. 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 alpha-induced phosphorylation of c-Jun NH(2)-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.

Original languageEnglish
Article number14199
Number of pages21
JournalPLoS ONE
Volume5
Issue number12
DOIs
Publication statusPublished - 2 Dec 2010

Keywords

  • ACTIVATED-RECEPTOR-GAMMA
  • DEPENDENT KINASE INHIBITORS
  • BINDING PROTEIN-ALPHA
  • STROMAL CELL CLONE
  • ADIPOCYTE DIFFERENTIATION
  • TRANSCRIPTION FACTORS
  • PPAR-GAMMA
  • HORMONE-RECEPTOR
  • ENERGY-BALANCE
  • C/EBP-ALPHA

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