title: Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice.
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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hirotsu
authors.forename: Chika
authors.initials: C
authors.lastname: Higashi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yagishita
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsuyama
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D051259:MafG Transcription Factor / Q000235:genetics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051265:NF-E2-Related Factor 1 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics; D013045:Species Specificity; D014158:Transcription, Genetic
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D051259:MafG Transcription Factor; C491247:Mafg protein, mouse; D051265:NF-E2-Related Factor 1; D012097:Repressor Proteins