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Background  The  Nuclear Receptor 2F2  ( NR2F2 / COUP-TFII ) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses  NR2F2  gene expression in pancreatic β-cells. The  cis -regulatory region of the  NR2F2  promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control  NR2F2  gene transcription and to evaluate the effect of  NR2F2  promoter variation on glucose homeostasis in humans.    Methodology/Principal Findings  Regulation of the  NR2F2  promoter was assessed using gene reporter assays, ChIP and gel shift experiments. The effects of variation at SNP rs3743462 in  NR2F2  on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4α activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried the rs3743462 T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levels and lower HOMA-IR index. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased  NR2F2  gene expression.    Conclusions/Significance  The rs3743462 polymorphism affects glucose-responsive  NR2F2  promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans.

Glucose-Dependent Regulation of NR2F2 Promoter and Influence of SNP-rs3743462 on Whole Body Insulin Sensitivity