RTEF-1 Attenuates Blood Glucose Levels by Regulating Insulin-Like Growth Factor Binding Protein-1 in the Endothelium

Rationale: 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 (RTEF-1-/-). Methods and 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, correlating with decreased IGFBP-1 levels. In contrast, vascular endothelial-cadherin (VE-Cad)/RTEF-1 overexpressing transgenic mice demonstrated improved glucose clearance and insulin sensitivity in response to a high fat diet. Furthermore, we demonstrated that RTEF-1 up-regulates IGFBP-1 through selectively binding and promoting transcription from the insulin response element (IRE) site. Insulin prevented RTEF-1 expression and significantly inhibited IGFBP-1 transcription in endothelial cells in a dose-dependent fashion. Conclusions: To our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an IRE 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 understanding the role of vascular endothelial cells in metabolism.