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Insulin resistance is a cellular antioxidant defense mechanism.

ABSTRACT: We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.

SUBMITTER: Hoehn KL

PROVIDER: S-EPMC2764908 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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Insulin resistance is a cellular antioxidant defense mechanism.

Hoehn Kyle L KL Salmon Adam B AB Hohnen-Behrens Cordula C Turner Nigel N Hoy Andrew J AJ Maghzal Ghassan J GJ Stocker Roland R Van Remmen Holly H Kraegen Edward W EW Cooney Greg J GJ Richardson Arlan R AR James David E DE

Proceedings of the National Academy of Sciences of the United States of America 20090930 42

We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rap ...[more]

PMID: 19805130

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Project description:ObjectivesTo test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury.DesignRandomized and controlled laboratory investigation in mice and cell culture.SettingUniversity laboratory.SubjectsC57BL/6J mice.InterventionsMice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury.Measurements and main resultsThree-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury.ConclusionsAmifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of ventilator-induced lung injury in critically ill patients subjected to extended mechanical ventilation.

Project description:Metalloid contamination, such as arsenic poisoning, poses a significant environmental problem, reducing plant productivity and putting human health at risk. Phytohormones are known to regulate arsenic stress; however, the function of strigolactones (SLs) in arsenic stress tolerance in rice is rarely investigated. Here, we investigated shoot responses of wild-type (WT) and SL-deficient d10 and d17 rice mutants under arsenate stress to elucidate SLs' roles in rice adaptation to arsenic. Under arsenate stress, the d10 and d17 mutants displayed severe growth abnormalities, including phenotypic aberrations, chlorosis and biomass loss, relative to WT. Arsenate stress activated the SL-biosynthetic pathway by enhancing the expression of SL-biosynthetic genes D10 and D17 in WT shoots. No differences in arsenic levels between WT and SL-biosynthetic mutants were found from Inductively Coupled Plasma-Mass Spectrometry analysis, demonstrating that the greater growth defects of mutant plants did not result from accumulated arsenic in shoots. The d10 and d17 plants had higher levels of reactive oxygen species, water loss, electrolyte leakage and membrane damage but lower activities of superoxide dismutase, ascorbate peroxidase, glutathione peroxidase and glutathione S-transferase than did the WT, implying that arsenate caused substantial oxidative stress in the SL mutants. Furthermore, WT plants had higher glutathione (GSH) contents and transcript levels of OsGSH1, OsGSH2, OsPCS1 and OsABCC1 in their shoots, indicating an upregulation of GSH-assisted arsenic sequestration into vacuoles. We conclude that arsenate stress activated SL biosynthesis, which led to enhanced arsenate tolerance through the stimulation of cellular antioxidant defense systems and vacuolar sequestration of arsenic, suggesting a novel role for SLs in rice adaptation to arsenic stress. Our findings have significant implications in the development of arsenic-resistant rice varieties for safe and sustainable rice production in arsenic-polluted soils.

Project description:Oxidative stress is a key pathogenic factor in both neurogenerative and metabolic diseases. However, its contribution in the brain complications of insulin resistance is still not well understood. Therefore, the aim of this study was the evaluation of redox homeostasis and oxidative damage in the hypothalamus and cerebral cortex of insulin-resistant and control rats. 16 male Wistar rats were divided into two equal groups (n = 8): the control and high fat diet group (HFD). Prooxidant enzymes (xanthine oxidase and NADPH oxidase); enzymatic and nonenzymatic antioxidants [glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase-1 (SOD-1), and uric acid (UA)]; and oxidative damage products [advanced glycation end products (AGE), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] as well as the total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and total ferric reducing ability of sample (FRAP) were evaluated in the hypothalamus and cerebral cortex as well as serum/plasma of HFD-fed and control rats. The activity of prooxidant enzymes was significantly increased in the cerebral cortex and hypothalamus of HFD-fed rats vs. control rats. Additionally, we have showed enhanced antioxidant efficiency in the hypothalamus (?CAT, ?UA, ?TAC, and ?FRAP) and cerebral cortex (?GPx, ?CAT, ?SOD-1, ?UA, ?TAC, and ?FRAP) of HFD-fed rats. All of the oxidative damage markers (AGE, 4-HNE, MDA, 8-OHdG, and OSI) were significantly increased in the cerebral cortex of insulin-resistant rats, while only 4-HNE and MDA were markedly higher in the hypothalamus of the HFD group. Summarizing, the results of our study indicate an adaptive brain response to the increased production of free radicals under insulin resistance conditions. Despite the increase in antioxidative defense systems, this mechanism does not protect both brain structures from oxidative damages. However, the cerebral cortex is more susceptible to oxidative stress caused by HFD.

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Insulin resistance is a cellular antioxidant defense mechanism.

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Insulin resistance is a cellular antioxidant defense mechanism.

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