Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice

Nrf1 (NF-E2-related factor 1) is a basic region leucine zipper-type transcription factor belonging to the CNC (cap-'n'-collar) family. Major pathophysiological contribution of Nrf1 remains unclear. As single nucleotide polymorphism rs3764400 in 5′-flanking region of NRF1 gene appears to associate with obesity, in this study, we focused on the Nrf1 function on metabolism. We found that the risk C allele of rs3764400 increased NRF1 gene transcriptional activity compared with the T allele in hepatoma cell lines. Therefore, we newly established Nrf1 transgenic (Nrf1-Tg) mouse lines and examined roles that Nrf1 plays on the obesity and metabolism. Unexpectedly, Nrf1 over-expression repressed bodyweight gain in both lean and diet-induced obesity mice. Of note, Nrf1-Tg mice showed rise in blood glucose levels; Nrf1 strongly reduced glucose infusion rate in euglycemic-hyperinsulinemic clamp test and increased blood glucose levels in insulin tolerance test, indicating that Nrf1 induces insulin resistance in mice. Nrf1 repressed insulin-regulated glycolysis-related gene expression and gave rise to loss of glucose-6-phosphate and fructose-6-phosphate contents in liver. Consistently, Nrf1 heterozygote improved impaired glucose regulations in diet-induced obesity model. These results showed that Nrf1 contributes to metabolic regulation, which gain-of-function develops diabetes mellitus in mice.