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

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.

SUBMITTER: Tsuzuki T

PROVIDER: S-EPMC4501761 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Tsuzuki Takamasa T Shinozaki Shohei S Nakamoto Hideko H Kaneki Masao M Goto Sataro S Shimokado Kentaro K Kobayashi Hiroyuki H Naito Hisashi H

PloS one 20150714 7

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. ...[more]

PMID: 26172834

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Project description:RationaleWe have previously shown that innate immunity is necessary for transdifferentiation of fibroblasts to endothelial cells. A major signaling molecule involved in innate immunity is inducible nitric oxide synthase (iNOS). Accordingly, we hypothesized that iNOS-generated nitric oxide (NO) might enhance transdifferentiation.ObjectiveTo elucidate the role of NO in epigenetic plasticity during transdifferentiation.Methods and resultsWe exposed the BJ fibroblasts to transdifferentiation formulation that included endothelial growth factors and innate immune activator polyinosinic:polycytidylic acid to induce endothelial cells. Generation of transdifferentiated endothelial cells was associated with iNOS expression and NO elaboration. In the absence of polyinosinic:polycytidylic acid, or in the presence of antagonists of NFκB (nuclear factor kappa B) or iNOS activity, NO synthesis and induce endothelial cell generation was reduced. Furthermore, genetic knockout (in murine embryonic fibroblasts) or siRNA knockdown (in BJ fibroblasts) of iNOS nearly abolished transdifferentiation, an effect that could be reversed by iNOS overexpression. Notably, polyinosinic:polycytidylic acid induced nuclear localization of iNOS, and its binding to, and nitrosylation of, the epigenetic modifier ring finger protein 1A (RING1A) as assessed by immunostaining, Co-IP, and mass spectrometry. Nitrosylation of RING1A reduced its binding to chromatin and reduced global levels of repressive histone marker H3K27 trimethylation. Overexpression of a mutant form of RING1A (C398A) lacking the nitrosylation site almost abrogated transdifferentiation.ConclusionsOverall, our data indicate that during transdifferentiation, innate immune activation increases iNOS generation of NO to S-nitrosylate RING1A, a key member of the polycomb repressive complex. Nitrosylation of RING1A reduces its binding to chromatin and decreases H3K27 trimethylation level. The release of epigenetic repression by nitrosylation of RING1A is critical for effective transdifferentiation.

Project description:Background: Adolescence is a period of time characterized by the onset of puberty and is marked by cognitive and social developments and gross physical changes that can play a role in athletic performance. Sex differences are present with differences in body size, height, physiology and behavior which contribute to differences in athletic performance as well. Pre-clinical studies representing this active group are lacking. Methods: Acute and chronic effects of exercise were evaluated. Male and female adolescent rats were given voluntary access to a running wheel for 10 consecutive days. Running behavior (males and females) and estrous cycling (females only) were analyzed daily. A second group was given 10 days of voluntary access to a running wheel, then rested for 10 days to determine the long-term effects of exercise on the adolescent brain. Brain and muscle tissue were harvested at 10 and 20 day time points to understand exercise-dependent changes in mitochondrial activity and neuroplasticity. Animal cohorts were carried out at two different sites: University of California Los Angeles and Pepperdine University. Results: On average, running distance, intensity of run, and length of running bout increased for both male and female rats across the 10 days measured. Females ran significantly further and for longer intervals compared to males. Cortical and muscle expression of PGC1α showed similar levels at 10 days regardless of sex and exercise. There was a significant increase in expression at 20 days in all groups correlating with body size (p's < 0.05). Cortical and hippocampal levels of BDNF were similar across all groups, however, BDNF was significantly higher in exercised females at the acute compared to long-term time point. Discussion: Adolescent rats allowed 10 days of exercise show changes in physiologic function. There are sex differences in running behavior not impacted by sex hormones. These results are important to further our understanding of how exercise impacts the adolescent brain.

Project description:Voluntary exercise increases stress resistance by modulating stress-responsive neurocircuitry, including brainstem serotonergic systems. However, it remains unknown how exercise produces adaptations to serotonergic systems. Recruitment of serotonergic systems during repeated, daily exercise could contribute to the adaptations in serotonergic systems following exercise, but whether repeated voluntary exercise recruits serotonergic systems is unknown. In this study, we investigated the effects of six weeks of voluntary or forced exercise on rat brain serotonergic systems. Specifically, we analyzed c-Fos and FosB/?FosB as markers of acute and chronic cellular activation, respectively, in combination with tryptophan hydroxylase, a marker of serotonergic neurons, within subregions of the dorsal raphe nucleus using immunohistochemical staining. Compared to sedentary controls, rats exposed to repeated forced exercise, but not repeated voluntary exercise, displayed decreased c-Fos expression in serotonergic neurons in the rostral dorsal portion of the dorsal raphe nucleus (DRD) and increased c-Fos expression in serotonergic neurons in the caudal DR (DRC), and interfascicular part of the dorsal raphe nucleus (DRI) during the active phase of the diurnal activity rhythm. Similarly, increases in c-Fos expression in serotonergic neurons in the DRC, DRI, and ventral portion of the dorsal raphe nucleus (DRV) were observed in rats exposed to repeated forced exercise, compared to rats exposed to repeated voluntary exercise. Six weeks of forced exercise, relative to the sedentary control condition, also increased FosB/?FosB expression in DRD, DRI, and DRV serotonergic neurons. While both voluntary and forced exercise increase stress resistance, these results suggest that repeated forced exercise, but not repeated voluntary exercise, increases activation of DRI serotonergic neurons, an effect that may contribute to the stress resistance effects of forced exercise. These results also suggest that mechanisms of exercise-induced stress resistance may differ depending on the controllability of the exercise.

Dataset Information

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

Publications

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

Similar Datasets

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