Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation.

Hobby Aggarwal,Jiaur R Gayen,Kumaravelu Jagavelu,Pragati Singh,Madhu Dikshit,Priya Pathak

doi:10.3390/antiox9080736

Abstract

iNOS, an important mediator of inflammation, has emerged as an important metabolic regulator. There are conflicting observations on the incidence of insulin resistance (IR) due to hyperglycemia/dyslipidemia in iNOS−/− mice. There are reports that high fat diet (HFD) fed mice exhibited no change, protection, or enhanced susceptibility to IR. Similar observations were also reported for low fat diet (LFD) fed KO mice. In the present study chow fed iNOS−/− mice were examined for the incidence of IR, and metabolic perturbations, and also for the effect of sodium nitrite supplementation (50 mg/L). In IR-iNOS−/− mice, we observed significantly higher body weight, BMI, adiposity, blood glucose, HOMA-IR, serum/tissue lipids, glucose intolerance, enhanced gluconeogenesis, and disrupted insulin signaling. Expression of genes involved in hepatic and adipose tissue lipid uptake, synthesis, oxidation, and gluconeogenesis was upregulated with concomitant downregulation of genes for hepatic lipid excretion. Nitrite supplementation restored NO levels, significantly improved systemic IR, glucose tolerance, and also reduced lipid accumulation by rescuing hepatic insulin sensitivity, glucose, and lipid homeostasis. Obesity, gluconeogenesis, and adipose tissue insulin signaling were only partially reversed in nitrite supplemented iNOS−/− mice. Our results thus demonstrate that nitrite supplementation to iNOS−/− mice improves insulin sensitivity and metabolic homeostasis, thus further highlighting the metabolic role of iNOS.

Highlights

Nitric oxide (NO), a pleiotropic gaseous signaling molecule, plays an important role in the cardiovascular and metabolic regulations
The relative liver and adipose tissue weights were higher in iNOS−/− mice as compared to wild type fed (WT) (Figure 1L)
Circulating total cholesterol, triglycerides, non-esterified free fatty acids (NEFA), and low density lipoprotein (LDL) were significantly more in iNOS−/− mice while HDL levels were comparable to WT mice (Figure 1O–R and Figure S1K)

Summary

Introduction

Nitric oxide (NO), a pleiotropic gaseous signaling molecule, plays an important role in the cardiovascular and metabolic regulations. Genetic polymorphism at the iNOS gene (14-repeat allele) is linked to increased iNOS activity which confers selective advantage to diabetic individuals. This points towards the protective role of constitutive iNOS in preventing or delaying the pathological alterations in diabetes [14,15]. Studies from our group and others on the effect of iNOS derived NO on endothelium functionality have shown that acetylcholine [16] and insulin [17] mediated vasorelaxation was significantly preserved in obese iNOS−/− mice, which was independent of IR, dyslipidemia or hyperglycemia, blood pressure, or oxidative stress. Reduction in NO bioavailability contributes to the pathogenesis of hyperlipidemia, endothelial dysfunction, atherosclerosis, hypertension, diabetes, and obesity [18,19,20]

Results

Discussion

Conclusion