Antioxidants preserve redox balance and inhibit c-Jun-N-terminal kinase pathway while improving insulin signaling in fat-fed rats: evidence for the role of oxidative stress on IRS-1 serine phosphorylation and insulin resistance

Abstract

The oxidative stress-sensitive c-Jun-N-terminal kinase (JNK) pathway is known to be activated in diabetic condition and is involved in the progression of insulin resistance. However, the effect of antioxidants on JNK pathway and insulin resistance has not been investigated. The present study was aimed to investigate the effect of antioxidants on redox balance, insulin sensitivity, and JNK pathway in high-fat-fed rats. Male Wistar rats were divided into four groups: the control group -received a rodent chow; controlCantioxidant group -fed with rodent chow supplemented with 0 . 2% (w/w) vitamin E, 0 . 3% (w/w) vitamin C, and 0 . 5% (w/w) a-lipoic acid; high-fat groupreceived high-fat diet; and high fatCantioxidant group -fed with high-fat diet supplemented with above antioxidants. Fat feeding to rats for 9 weeks significantly increased IRS-1 serine phoshorylation, reduced insulin-stimulated IRS-1 tyrosine phosphorylation and insulin sensitivity. High-fat diet also impaired redox balance and activated the redox-sensitive serine kinase -JNK pathway. Antioxidant supplementation along with high-fat diet preserved the free radical defense system, inhibited the activation of JNK pathway, and improved insulin signaling and insulin sensitivity. The present study shows for the first time that antioxidants inhibit JNK pathway and IRS-1 serine phosphorylation while improving insulin sensitivity in fat-fed rats. These findings implicate the beneficial effect of antioxidants in obesity-/dyslipidemia-induced insulin resistance in humans.

Vitamin C in the Treatment and/or Prevention of Obesity

“…All these outcomes can constitute a bridge between weight reduction and VC antioxidant features (25). e) Glucose metabolism As described before, it has been observed that an antioxidant cocktail (including VC) induced significant improvement in insulin-sensitivity in the adipose tissue of HFD-fed rats (68). These outcomes were related with improvements in cellular insulin signaling by modification of the IRS-1/JNK cellular pathway.…”

“…Oxidative stress Important effects on redox balance in adipose tissue from HFD-fed obese rats (68) Lower liver malondialdehyde levels in rats that consume HFD supplemented with VC than rats fed on HFD alone…”

“…Glucose metabolism Antioxidant cocktail (including VC) induced insulin-sensitivity in adipose tissue from HFD-fed rats, modulating IRS-1/JNK signaling (68) VC treatment inhibited glucose uptake on isolated adipocytes from both lean and obese animals (33,66) IRS-3 gene expression inhibition on isolated adipocytes from lean animals by VC treatment (33) Apelin gene expression inhibition by VC treatment on adipocytes isolated from both lean and diet-induced obese rats, and on a murine model of adipocytemacrophage crosstalk (66,80) VC supplementation to HFD induced improvement in insulin sensitivity as measured as glucose and insulin plasma levels, and HOMA index, in rats, at 2 and 8 wk of treatment (26, 29)…”

“…Studies in animals have reported that an antioxidant cocktail, containing VC, has important ameliorating effects on insulin-resistance and on redox imbalance in adipose tissue from HF-fed rats (68). These insulinsensitizing features were driven through insulin receptor substrate-1 (IRS-1)/c-Jun N-terminal kinase (JNK) pathway modulation.…”

Heat Treatment Improves Glucose Tolerance and Prevents Skeletal Muscle Insulin Resistance in Rats Fed a High-Fat Diet

“…Increased oxidative stress has been strongly implicated as a cause of diet-induced insulin resistance (32,33). Activation of stress-induced kinases such as JNK, glycogen synthase kinase 3␤, IKK-␤, and protein kinase C (34,35) can cause inhibitory phosphorylation of IRS-1 on serine 307. A decrease in muscle oxidative stress with heat treatment could result in decreased stress kinase activation and improved insulin signaling.…”