Article

Diabetologia

, Volume 54, Issue 4, pp 922-934

First online:

Oltipraz upregulates the nuclear respiratory factor 2 alpha subunit (NRF2) antioxidant system and prevents insulin resistance and obesity induced by a high-fat diet in C57BL/6J mice

  • Z. YuAffiliated withGuandong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, Public Health Institute, Sun Yat-Sen University
  • , W. ShaoAffiliated withBanting and Best Diabetes Centre, Faculty of Medicine, University of TorontoDepartment of Medicine, Faculty of Medicine, University of Toronto10-354 Toronto Medical Discovery Tower, The MaRS Building, Toronto General Research Institute, University Health Network
  • , Y. ChiangAffiliated withBanting and Best Diabetes Centre, Faculty of Medicine, University of TorontoDepartment of Physiology, University of Toronto
  • , W. FoltzAffiliated withThe STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Hospital, University Health Network
  • , Z. ZhangAffiliated withNatural Science Foundation of China
  • , W. LingAffiliated withGuandong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, Public Health Institute, Sun Yat-Sen University
  • , I. G. FantusAffiliated withBanting and Best Diabetes Centre, Faculty of Medicine, University of TorontoDepartment of Medicine, Faculty of Medicine, University of Toronto10-354 Toronto Medical Discovery Tower, The MaRS Building, Toronto General Research Institute, University Health NetworkDepartment of Physiology, University of Toronto
  • , T. JinAffiliated withGuandong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, Public Health Institute, Sun Yat-Sen UniversityBanting and Best Diabetes Centre, Faculty of Medicine, University of TorontoDepartment of Medicine, Faculty of Medicine, University of Toronto10-354 Toronto Medical Discovery Tower, The MaRS Building, Toronto General Research Institute, University Health NetworkDepartment of Physiology, University of Toronto Email author 

Abstract

Aims/hypothesis

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/interpretation

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.

Keywords

High fat Insulin resistance NRF2 Obesity Oltipraz Oxidative stress