Voluntary Exercise Can Ameliorate Insulin Resistance by Reducing iNOS-Mediated S-Nitrosylation of Akt in the Liver in Obese Rats.

Takamasa Tsuzuki,Shohei Shinozaki,Hiroyuki Kobayashi,Sataro Goto,Hisashi Naito,Hideko Nakamoto,Kentaro Shimokado,Masao Kaneki,Zane Andrews

doi:10.1371/journal.pone.0132029

Abstract

Voluntary exercise can ameliorate insulin resistance. The underlying mechanism, however, remains to be elucidated. We previously demonstrated that inducible nitric oxide synthase (iNOS) in the liver plays an important role in hepatic insulin resistance in the setting of obesity. In this study, we tried to verify our hypothesis that voluntary exercise improves insulin resistance by reducing the expression of iNOS and subsequent S-nitrosylation of key molecules of glucose metabolism in the liver. Twenty-one Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non-diabetic control Long-Evans Tokushima Otsuka (LETO) rats were randomly assigned to a sedentary group or exercise group subjected to voluntary wheel running for 20 weeks. The voluntary exercise significantly reduced the fasting blood glucose and HOMA-IR in the OLETF rats. In addition, the exercise decreased the amount of iNOS mRNA in the liver in the OLETF rats. Moreover, exercise reduced the levels of S-nitrosylated Akt in the liver, which were increased in the OLETF rats, to those observed in the LETO rats. These findings support our hypothesis that voluntary exercise improves insulin resistance, at least partly, by suppressing the iNOS expression and subsequent S-nitrosylation of Akt, a key molecule of the signal transduction pathways in glucose metabolism in the liver.

Highlights

With the excess consumption of food and physical inactivity as well as advancing population aging, the incidence of lifestyle-related diseases, including metabolic syndrome, is rapidly and PLOS ONE | DOI:10.1371/journal.pone.0132029 July 14, 2015Voluntary Exercise Reduces S-Nitrosylation of Akt design, data collection and analysis, decision to publish or preparation of the manuscript
Significant differences were found in the whole-body weight and epididymal fat weight of the OLEFT rats at 25 weeks of age after overnight fasting compared to those observed in the Long-Evans Tokushima Otsuka (LETO) rats under sedentary conditions (S1A to S1C Fig)
In order to assess other mechanisms involved in the pathogenesis of hepatic insulin resistance, we evaluated the triglyceride content and the expression of molecules that participate in lipogenesis in the liver, such as sterol-regulatory element binding protein-1 (Srebp-1), stearoyl coenzyme A desaturase-1 (Scd-1), acetyl-CoA carboxylase (Acc), fatty acid synthase (Fas) and glycerol-3-phosphate acyltransferase 2 (Gpat2)

Summary

Introduction

With the excess consumption of food and physical inactivity as well as advancing population aging, the incidence of lifestyle-related diseases, including metabolic syndrome, is rapidly and PLOS ONE | DOI:10.1371/journal.pone.0132029 July 14, 2015. We previously showed that regular exercise increases the intracellular GSH content and decreases chronic low-level inflammation in the liver in aged rats [11]. OLETF and Long-Evans Tokushima Otsuka (LETO) rats are well studied with respect to obesity-induced insulin resistance and the beneficial effects of regular physical activity [13, 14, 17]. Numerous studies have shown that regular exercise prevents obesity and insulin resistance, whereas sedentary behavior increases the risk of metabolic syndrome [18,19,20,21,22]. We hypothesized that voluntary exercise improves insulin resistance by reducing the expression of iNOS and subsequent S-nitrosylation of key molecules of glucose metabolism in the liver. In order to evaluate this hypothesis, we tested whether voluntary exercise prevents hepatic insulin resistance in OLETF and LETO rats

Materials and Methods

Results

Discussion