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

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

doi:10.1371/journal.pone.0132029

Cited by 30 publications

(24 citation statements)

References 67 publications

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“…In this sense, the increase of blood glucose, insulin and HOMA-2%S after neuronal injury in the sedentary FPI group corroborates data from obese animal and human studies indicating that hepatic cytokine expression (TNF-α) activates intracellular JNK and phosphorylate insulin receptor substrate (IRS-1) at serine residues (Cai et al 2005;Moschen & Tilg, 2008). Our experimental data also suggest that acute stress, such as TBI, may lead to hyperglycaemia, in the absence of diabetes, and also that strategies such as exercise training can enhance glucose control and reduce damage as a result of hyperglycaemia to several cells (Tsuzuki et al 2015;Shi et al 2016). Indeed, our experimental protocol of exercise training protected against blood glucose, insulin and HOMA-2%S increases, as well as hepatic immunoreactivity of pJNK increase, and also pIRS and pAKT decreases after neuronal injury.…”

Section: Discussionsupporting

confidence: 87%

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Previous physical exercise alters the hepatic profile of oxidative‐inflammatory status and limits the secondary brain damage induced by severe traumatic brain injury in rats

Castro¹,

Ferreira²,

Busanello³

et al. 2017

The Journal of Physiology

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Although systemic responses have been described after traumatic brain injury (TBI), little is known regarding potential interactions between brain and peripheral organs after neuronal injury. Accordingly, we aimed to investigate whether a peripheral oxidative/inflammatory response contributes to neuronal dysfunction after TBI, as well as the prophylactic role of exercise training. Animals were submitted to fluid percussion injury after 6 weeks of swimming training. Previous exercise training increased mRNA expression of X receptor alpha and ATP-binding cassette transporter, and decreased inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-α and interleukin (IL)-6 expression per se in liver. Interestingly, exercise training protected against hepatic inflammation (COX-2, iNOS, TNF-α and IL-6), oxidative stress (decreases in non-protein sulfhydryl and glutathione, as well as increases in 2',7'-dichlorofluorescein diacetate oxidation and protein carbonyl), which altered hepatic redox status (increases in myeloperoxidase and superoxide dismutase activity, as well as inhibition of catalase activity) mitochondrial function (decreases in methyl-tetrazolium and Δψ, as well as inhibition of citrate synthase activity) and ion gradient homeostasis (inhibition of Na ,K -ATPase activity inhibition) when analysed 24 h after TBI. Previous exercise training also protected against dysglycaemia, impaired hepatic signalling (increase in phosphorylated c-Jun NH2-terminal kinase, phosphorylated decreases in insulin receptor substrate and phosphorylated AKT expression), high levels of circulating and neuronal cytokines, the opening of the blood-brain barrier, neutrophil infiltration and Na ,K -ATPase activity inhibition in the ipsilateral cortex after TBI. Moreover, the impairment of protein function, neurobehavioural (neuromotor dysfunction and spatial learning) disability and hippocampal cell damage in sedentary rats suggests that exercise training also modulates peripheral oxidative/inflammatory pathways in TBI, which corroborates the ever increasing evidence regarding health-related outcomes with respect to a physically active lifestyle.

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Section: Discussionsupporting

confidence: 87%

“…Our experimental data also suggest that acute stress, such as TBI, may lead to hyperglycaemia, in the absence of diabetes, and also that strategies such as exercise training can enhance glucose control and reduce damage as a result of hyperglycaemia to several cells (Tsuzuki et al . ; Shi et al . ).…”

Section: Discussionmentioning

confidence: 97%

Previous physical exercise alters the hepatic profile of oxidative‐inflammatory status and limits the secondary brain damage induced by severe traumatic brain injury in rats

Castro¹,

Ferreira²,

Busanello³

et al. 2017

The Journal of Physiology

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“…OLETF rats develop hyperglycemia after 18 weeks of age, and most OLETF rats have diabetes at 25 weeks of age [ 15 , 17 ]. Our group also previously confirmed that OLETF rats develop diabetes at 25 weeks of age [ 18 ]. At 5 weeks of age, the rats were assigned randomly to four groups: OLETF sedentary group (O-Sed; n = 11), OLETF exercise group (O-Ex; n = 10), LETO sedentary group (L-Sed; n = 9), and LETO exercise group (L-Ex; n = 9).…”

Section: Methodssupporting

confidence: 74%

Effects of voluntary running exercise on bone histology in type 2 diabetic rats

et al. 2018

Self Cite

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The incidence of obesity in children and adolescents, which may lead to type 2 diabetes, is increasing. Exercise is recommended to prevent and improve diabetes. However, little is known about the bone marrow environment at the onset of diabetes in the young, and it is unclear whether exercise training is useful for maintaining bone homeostasis, such as mechanical and histological properties. Thus, this study clarified the histological properties of bone and whether exercise contributes to maintaining bone homeostasis at the onset of type 2 diabetes in rats. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF; n = 21) rats as a diabetic model and Long-Evans Tokushima Otsuka (LETO; n = 18) rats as a control were assigned randomly to four groups: the OLETF sedentary group (O-Sed; n = 11), OLETF exercise group (O-Ex; n = 10), LETO sedentary group (L-Sed; n = 9), and LETO exercise group (L-Ex; n = 9). All rats in the exercise group were allowed free access to a steel running wheel for 20 weeks (5–25 weeks of age). In the glucose tolerance test, blood glucose level was higher in the O-Sed group than that in the L-Sed and L-Ex groups, and was markedly suppressed by the voluntary running exercise of O-Ex rats. The energy to fracture and the two-dimensional bone volume at 25 weeks of age did not differ significantly among the groups, though the maximum breaking force and stiffness were lower in OLETF rats. However, bone marrow fat volume was greater in O-Sed than that in L-Sed and L-Ex rats, and was markedly suppressed by wheel running in the O-Ex rats. Our results indicate that exercise has beneficial effects not only for preventing diabetes but also on normal bone remodeling at an early age.

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“…Thus, collectively, our findings suggest that S-nitrosation of IR and Akt supersedes its potential anti-inflammatory effects and therefore contributes to obesity physiopathology. Importantly, exercise-mediated neurological control of weight loss has been associated with attenuation of hypothalamic inflammation and protection of POMC neurons from apoptosis, resulting in increased insulin and leptin sensitivity 45 – 48 . Consistent with these results we observed that exercise decreased S-nitrosation of IR and Akt in hypothalamus and reduction in food intake of DIO mice.…”

Section: Discussionmentioning

confidence: 99%

iNOS promotes hypothalamic insulin resistance associated with deregulation of energy balance and obesity in rodents

Katashima

Silva

Lenhare

et al. 2017

Sci Rep

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Inducible nitric oxide (iNOS)-mediated S-nitrosation of the metabolic signaling pathway has emerged as a post-translational modification that triggers insulin resistance in obesity and aging. However, the effects of S-nitrosation in controlling energy homeostasis are unknown. Thus, in the present study we aimed to evaluate the effects of S-nitrosation in insulin signaling pathway in the hypothalamus of rodents. Herein, we demonstrated that the intracerebroventricular infusion of the nitric oxide (NO) donor S-nitrosoglutathione (GSNO) promoted hypothalamic insulin signaling resistance and replicated the food intake pattern of obese individuals. Indeed, obesity induced S-nitrosation of hypothalamic IR and Akt, whereas inhibition of iNOS or S-nitrosation of insulin signaling pathway protected against hypothalamic insulin resistance and normalized energy homeostasis. Overall, these findings indicated that S-nitrosation of insulin signaling pathway is required to sustain hypothalamic insulin resistance in obesity.

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

Cited by 30 publications

References 67 publications

Previous physical exercise alters the hepatic profile of oxidative‐inflammatory status and limits the secondary brain damage induced by severe traumatic brain injury in rats

Previous physical exercise alters the hepatic profile of oxidative‐inflammatory status and limits the secondary brain damage induced by severe traumatic brain injury in rats

Effects of voluntary running exercise on bone histology in type 2 diabetic rats

iNOS promotes hypothalamic insulin resistance associated with deregulation of energy balance and obesity in rodents

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