title: Nrf2 represses FGF21 during long-term high-fat diet-induced obesity in mice.
abstract: OBJECTIVE
  Obesity is characterized by chronic oxidative stress. Fibroblast growth factor 21 (FGF21) has recently been identified as a novel hormone that regulates metabolism. NFE2-related factor 2 (Nrf2) is a transcription factor that orchestrates the expression of a battery of antioxidant and detoxification genes under both basal and stress conditions. The current study investigated the role of Nrf2 in a mouse model of long-term high-fat diet (HFD)-induced obesity and characterized its crosstalk to FGF21 in this process.
  
  
  METHODS
  Wild-type (WT) and Nrf2 knockout (Nrf2-KO) mice were fed an HFD for 180 days. During this period, food consumption and body weights were measured. Glucose metabolism was assessed by an intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test. Total RNA was prepared from liver and adipose tissue and was used for quantitative real-time RT-PCR. Fasting plasma was collected and analyzed for blood chemistries. The ST-2 cell line was used for transfection studies.
  
  
  RESULTS
  Nrf2-KO mice were partially protected from HFD-induced obesity and developed a less insulin-resistant phenotype. Importantly, Nrf2-KO mice had higher plasma FGF21 levels and higher FGF21 mRNA levels in liver and white adipose tissue than WT mice. Thus, the altered metabolic phenotype of Nrf2-KO mice under HFD was associated with higher expression and abundance of FGF21. Consistently, the overexpression of Nrf2 in ST-2 cells resulted in decreased FGF21 mRNA levels as well as in suppressed activity of a FGF21 promoter luciferase reporter.
  
  
  CONCLUSIONS
  The identification of Nrf2 as a novel regulator of FGF21 expands our understanding of the crosstalk between metabolism and stress defense.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Medical School, University of Patras, Patras, Greece.
authors.forename: Dionysios V
authors.initials: DV
authors.lastname: Chartoumpekis
authors.forename: Panos G
authors.initials: PG
authors.lastname: Ziros
authors.forename: Agathoklis I
authors.initials: AI
authors.lastname: Psyrogiannis
authors.forename: Athanasios G
authors.initials: AG
authors.lastname: Papavassiliou
authors.forename: Venetsana E
authors.initials: VE
authors.lastname: Kyriazopoulou
authors.forename: Gerasimos P
authors.initials: GP
authors.lastname: Sykiotis
authors.forename: Ioannis G
authors.initials: IG
authors.lastname: Habeos
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000209:etiology* / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors