Several recent studies on rodent models suggest that NR2F2 is involved in glucose homeostasis and in energy metabolism (
and L. Sabra-Makke et al.
in preparation). Interestingly, NR2F2
is also regulated by nutrients and hormones 
. For instance, its expression is repressed directly in response to exogenous insulin and indirectly in response to high glucose concentrations through enhanced insulin secretion in pancreatic β-cells 
In the present study, we showed that the proximal promoter of NR2F2
is responsive to changes in glucose concentrations. In INS-1 pancreatic β-cells, high glucose concentrations decreased both the HNF4α-dependent ChIP signal on the DR-1 DNA binding site and a DR-1-driven luciferase reporter gene transactivation. These findings were further supported by the co-repression of HNF4α
genes in the presence of 20 mM glucose concentrations in INS-1 β-cells as previously described for HNF4α expression in hepatocytes 
. Altogether our data suggest that the activation of NR2F2
gene expression in the fasted state, when insulin and glucose concentrations are at their lowest, results in part from the stimulation of HNF4α. Furthermore, we showed that allelic variation at rs3743462 in a conserved cis
-regulatory region of the distal NR2F2
promoter is associated with fasting insulin concentrations, the HOMA-IR index and adult height in non diabetic individuals in the DESIR study. These three phenotypic traits have previously been associated with metabolic health in various populations 
. The DESIR prospective cohort is a comprehensively phenotyped general population of middle-aged individuals, in which we previously analyzed several genetic variants with confirmed significant effects either on T2D risk or on glucose and lipid homeostasis quantitative traits 
. By assessing a genotype effect on continuous variables measured over the 9-years of follow-up in the study, we are quite confident of the validity of the associations between rs3743462 and the metabolic variables tested in this large general population. However, our follow-up study of these genetic associations in other European populations did not replicate these observations. The latest meta-analyses of fasting insulin and HOMA-IR from the MAGIC consortium dataset did not show evidence of associations for rs3743462 
. Furthermore, the GIANT meta-analysis of adult BMI did not reveal any association at genome-wide level significance between rs3743462 and adult BMI 
. The allelic change from T to C at the NR2F2
-rs3743462 polymorphism probably has modest effects on glucose homeostasis in vivo
. Such effects are very likely dependent on complex gene-environment interactions that have yet to be disentangled. Nevertheless, observation from the DESIR study, that variation within the distal promoter region of NR2F2
is associated with whole-body insulin sensitivity, is partly consistent with the phenotype of NR2F2
heterozygous knockout mice 
which show improved glucose homeostasis and increased energy expenditure. These mutant mice displayed normal fasted plasma glucose, lower fasted insulin concentrations and improved insulin sensitivity.
Interestingly, we showed in a pancreatic β-cell line that the presence of the rs3743462-C allele enhances NR2F2
binding to its distal promoter. Our NR2F2
fusion gene assay with the C-allele of the SNP resulted in a repression of gene activity compared to the T allele suggesting that the binding of NR2F2 to its distal promoter participates in decreasing NR2F2
expression. These observations are consistent with previous experiments where over-expression of NR2F2 decreased endogenous NR2F2 mRNA abundance in pancreatic β-cells 
, suggesting a possible negative feedback of NR2F2 on its own gene transcription. It would be interesting to test NR2F2 binding in vivo
but since it is the mutation that promotes increased NR2F2 binding it is not easy to realize these experiments.
We have shed light on the importance of both HNF4α and NR2F2 itself in the control of its expression and suggested an HNF4α-dependent site that contributes to regulate NR2F2 transcription in response to glucose concentrations changes. Our data are suggestive of a greater affinity of NR2F2 to control its own promoter in the presence of the rs3743462-C allele that is associated with whole-body insulin sensitivity in a general population of non diabetic individuals. The role of NR2F2 regulation in the aetiology of complex metabolic diseases, such as the metabolic syndrome and T2D has yet to be fully understood. In conclusion, our data suggest that NR2F2 might be a key factor in novel strategies aiming to prevent or treat some of the metabolic defects related to insulin resistance in humans.