title: RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium.
abstract: BACKGROUND
  Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in endothelial cell function by regulating angiogenesis; however, the mechanism underlying the role of RTEF-1 in the endothelium in vivo is not well defined.
  
  
  OBJECTIVE
  We investigated the biological functions of RTEF-1 by disrupting the gene that encodes it in mice endothelium -specific RTEF-1-deficient transgenic mice (RTEF-1(-/-)).
  
  
  RESULTS
  RTEF-1(-/-) mice showed significantly increased blood glucose levels and insulin resistance, accompanied by decreased levels of insulin-like growth factor binding protein-1 (IGFBP-1) mRNA in the endothelium and decreased serum IGFBP-1 levels. Additionally, the RTEF-1(-/-) phenotype was exacerbated when the mice were fed a high-fat diet, which correlated with decreased IGFBP-1 levels. In contrast, vascular endothelial cadherin/RTEF-1-overexpressing(1) transgenic mice (VE-Cad/RTEF1) demonstrated improved glucose clearance and insulin sensitivity in response to a high-fat diet. Furthermore, we demonstrated that RTEF-1 upregulates IGFBP-1 through selective binding and promotion of transcription from the insulin response element site. Insulin prevented RTEF-1 expression and significantly inhibited IGFBP-1 transcription in endothelial cells in a dose-dependent fashion.
  
  
  CONCLUSIONS
  To the best of our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an insulin response element and also mediates the effects of insulin on gene expression. These results show that RTEF-1-stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels. These findings provide the basis for novel insights into the transcriptional regulation of IGFBP-1 and contribute to our understanding of the role of vascular endothelial cells in metabolism.
authors: Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors: Angela F
authors: AF
authors: Messmer-Blust
authors: Melissa J
authors: MJ
authors: Philbrick
authors: Shuzhen
authors: S
authors: Guo
authors: Jiaping
authors: J
authors: Wu
authors: Ping
authors: P
authors: He
authors: Shaodong
authors: S
authors: Guo
authors: Jian
authors: J
authors: Li
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006309:Hearing / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; C032231:IGFBP1 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; C101204:Tead4 protein, mouse; D014157:Transcription Factors