title: Multiple roles for the non-coding RNA SRA in regulation of adipogenesis and insulin sensitivity.
abstract: Peroxisome proliferator-activated receptor-γ (PPARγ) is a master transcriptional regulator of adipogenesis. Hence, the identification of PPARγ 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 PPARγ and coactivates PPARγ-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 TNFα signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPARγ. 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 TNFα-induced phosphorylation of c-Jun NH(2)-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.
authors.affiliation: Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America. bxu@umich.edu
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gerin
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Miao
authors.forename: Dang
authors.initials: D
authors.lastname: Vu-Phan
authors.forename: Craig N
authors.initials: CN
authors.lastname: Johnson
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Xu
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: William P
authors.initials: WP
authors.lastname: Cawthorn
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Koenig
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000378:metabolism*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C405423:steroid receptor RNA activator; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005982:Glutathione Transferase; D005947:Glucose