title: Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet.
abstract: Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulating glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling.
authors.affiliation: Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
authors.forename: Yu-Kun Jennifer
authors.initials: YK
authors.lastname: Zhang
authors.forename: Kai Connie
authors.initials: KC
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000821:Animal Feed / Q000032:analysis; D000818:Animals; D001786:Blood Glucose; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage* / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006728:Hormones; D007328:Insulin / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009765:Obesity; D012313:RNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D003598:Cytoskeletal Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D006728:Hormones; D007328:Insulin; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012313:RNA