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

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 Z. Yu and W. Shao contributed equally to this study. Diabetologia (2011) 54:922-934 DOI 10.1007/s00125-010-2001 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. Electronic supplementary material

Susceptibility of Nrf2-Null Mice to Steatohepatitis and Cirrhosis upon Consumption of a High-Fat Diet Is Associated with Oxidative Stress, Perturbation of the Unfolded Protein Response, and Disturbance in the Expression of Metabolic Enzymes but Not with Insulin Resistance

“…Such outcomes, although conflicting with the majority of Nrf2 gain-of-function studies (37, 68, 69), are in agreement with other recent studies of long-term HF-fed Nrf2 −/− mice (39, 43). The increased strength of insulin signaling in both Nrf2 −/− livers and skeletal muscle possibly reflects impaired antioxidant capacity in the mutant animal that results in an increase in H 2 O 2 levels, which in turn increases inactivation of protein tyrosine phosphatase 1B that antagonizes insulin signaling (70).…”

Sulforaphane improves dysregulated metabolic profile and inhibits leptin-induced VSMC proliferation: Implications toward suppression of neointima formation after arterial injury in western diet-fed obese mice

“…From the present findings in HFHS diet-fed mice, it is apparent that SFN-mediated decrease in plasma leptin may in part be accountable for the observed decrease in plasma insulin and improvements in HOMA-IR value (an index of insulin resistance) and glucose tolerance. At this juncture, it is important to note that in HFD fed-mice, nrf2 inducers such as SFN, triterpenoid CDDO-imidazolide, and oltipraz attenuate weight gain and visceral adiposity [13, 64, 65] and prevent insulin resistance [65]. It is likely that SFN treatment in HSHS diet-fed mice (present study) inhibits the obese phenotype in a similar manner through nrf2 activation in adipocytes.…”

Curcumin represses mouse 3T3-L1 cell adipogenic differentiation via inhibiting miR-17-5p and stimulating the Wnt signalling pathway effector Tcf7l2

“…17, 45 Briefly, 5-week-old male C57BL/6 mice were purchased from the Charles River Laboratories (Montreal, Canada). After a 1-week acclimatization period, the mice were randomly divided to two groups with six mice per group: the chow diet group and the HFD group.…”