Transcription factor NF‐E2‐related factor 1 impairs glucose metabolism in mice. (6th July 2014) - Hirotsu, Yosuke
Abstract 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.