title: Oltipraz upregulates the nuclear factor (erythroid-derived 2)-like 2 [corrected](NRF2) antioxidant system and prevents insulin resistance and obesity induced by a high-fat diet in C57BL/6J mice.
abstract: OBJECTIVE
  We investigated whether oltipraz, a nuclear respiratory factor 2 alpha subunit (NRF2) activator, improves insulin sensitivity and prevents the development of obesity in mice.
  
  
  METHODS
  C57BL/6J mice were fed with a low-fat diet (10% of energy as fat), a high-fat diet (HFD) (45% of energy as fat) or a HFD with oltipraz for 28 weeks. The effects of oltipraz on body weight, fat content, glucose disposal, insulin signalling, metabolic profiles and endogenous NRF2 functional status in the three groups of mice were investigated.
  
  
  RESULTS
  Oltipraz prevented or significantly attenuated the effect of HFD on glucose disposal, body weight and fat gain. Impairment of protein kinase B/Akt phosphorylation in this HFD-fed mouse model in response to intraperitoneal insulin injection was observed in adipose tissue, but not in the muscles, accompanied by inhibition of AMP-activated protein kinase signalling and activation of p70S6 kinase, as well as reduced GLUT4 content. These defects were attenuated by oltipraz administration. Nuclear content of NRF2 in adipose tissue was reduced by HFD feeding, associated with increased Keap1 mRNA expression and reduced production of haem oxygenase-1 and superoxide dismutase, increased protein oxidation, decreased plasma reduced:oxidised glutathione ratio and the appearance of macrophage marker F4/80. These defects were also restored by oltipraz. Finally, oltipraz attenuated HFD-induced inducible nitric oxide synthase overproduction.
  
  
  CONCLUSIONS
  Impairment of the endogenous redox system is important in the development of obesity and insulin resistance in chronic HFD feeding. NRF2 activation represents a potential novel approach in the treatment and prevention of obesity and diabetes.
authors.affiliation: Guandong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, Public Health Institute, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: W
authors.initials: W
authors.lastname: Shao
authors.forename: Y
authors.initials: Y
authors.lastname: Chiang
authors.forename: W
authors.initials: W
authors.lastname: Foltz
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Ling
authors.forename: I G
authors.initials: IG
authors.lastname: Fantus
authors.forename: T
authors.initials: T
authors.lastname: Jin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D004041:Dietary Fats / Q000009:adverse effects*; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D011719:Pyrazines / Q000627:therapeutic use*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013871:Thiones; D013876:Thiophenes
chemical_list: D000975:Antioxidants; D004041:Dietary Fats; D051267:NF-E2-Related Factor 2; D011719:Pyrazines; D034741:RNA, Small Interfering; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz