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Redox Balance, Antioxidant Defense, and Oxidative Damage in the Hypothalamus and Cerebral Cortex of Rats with High Fat Diet-Induced Insulin Resistance.

ABSTRACT: 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.

SUBMITTER: Maciejczyk M

PROVIDER: S-EPMC6146783 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Redox Balance, Antioxidant Defense, and Oxidative Damage in the Hypothalamus and Cerebral Cortex of Rats with High Fat Diet-Induced Insulin Resistance.

Maciejczyk Mateusz M Żebrowska Ewa E Zalewska Anna A Chabowski Adrian A

Oxidative medicine and cellular longevity 20180906

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 (<i>n</i> = 8): the control and high fat diet group (HFD). Prooxidant enzym ...[more]

PMID: 30271528

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Project description:Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) belong to a group of primary immunodeficiency diseases (PI) characterized by premature aging, cerebral degeneration, immunoglobulin deficiency and higher cancer susceptibility. Despite the fact that oxidative stress has been demonstrated in vitro and in animal models of AT and NBS, the involvement of redox homeostasis disorders is still unclear in the in vivo phenotype of AT and NBS patients. Our study is the first to compare both enzymatic and non-enzymatic antioxidants as well as oxidative damage between AT and NBS subjects. Twenty two Caucasian children with AT and twelve patients with NBS were studied. Enzymatic and non-enzymatic antioxidants - glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase-1 (SOD) and uric acid (UA); redox status-total antioxidant capacity (TAC) and ferric reducing ability of plasma (FRAP); and oxidative damage products-8-hydroxy-2'-deoxyguanosine (8-OHdG), advanced glycation end products (AGE), advanced oxidation protein products (AOPP), 4-hydroxynonenal (4-HNE) protein adducts, and 8-isoprostanes (8-isop) were evaluated in serum or plasma samples. We showed that CAT, SOD and UA were significantly increased, while TAC and FRAP levels were statistically lower in the plasma of AT patients compared to controls. In NBS patients, only CAT activity was significantly elevated, while TAC was significantly decreased as compared to healthy children. We also showed higher oxidative damage to DNA (↑8-OHdG), proteins (↑AGE, ↑AOPP), and lipids (↑4-HNE, ↑8-isop) in both AT and NBS patients. Interestingly, we did not demonstrate any significant differences in the antioxidant defense and oxidative damage between AT and NBS patients. However, in AT children, we showed a positive correlation between 8-OHdG and the α-fetoprotein level as well as a negative correlation between 8-OHdG and IgA. In NBS, AGE was positively correlated with IgM and negatively with the IgG level. Summarizing, we demonstrated an imbalance in cellular redox homeostasis and higher oxidative damage in AT and NBS patients. Despite an increase in the activity/concentration of some antioxidants, the total antioxidant capacity is overwhelmed in children with AT and NBS and predisposes them to more considerable oxidative damage. Oxidative stress may play a major role in AT and NBS phenotype.

Project description:Many theories have been advanced to better understand why β cell function and structure relentlessly deteriorate during the course of type 2 diabetes (T2D). These theories include inflammation, apoptosis, replication, neogenesis, autophagy, differentiation, dedifferentiation, and decreased levels of insulin gene regulatory proteins. However, none of these have considered the possibility that endogenous self-repair of existing β cells may be an important factor. To examine this hypothesis, we conducted studies with female Zucker diabetic fatty rats fed a high-fat diet (HFD) for 1, 2, 4, 7, 9, 18, or 28 days, followed by a return to regular chow for 2-3 weeks. Repair was defined as reversal of elevated blood glucose and of inappropriately low blood insulin levels caused by a HFD, as well as reversal of structural damage visualized by imaging studies. We observed evidence of functional β cell damage after a 9-day exposure to a HFD and then repair after 2-3 weeks of being returned to normal chow (blood glucose [BG] = 348 ± 30 vs. 126 ± 3; mg/dl; days 9 vs. 23 day, P < 0.01). After 18- and 28-day exposure to a HFD, damage was more severe and repair was less evident. Insulin levels progressively diminished with 9-day exposure to a HFD; after returning to a regular diet, insulin levels rebounded toward, but did not reach, normal values. Increase in β cell mass was 4-fold after 9 days and 3-fold after 18 days, and there was no increase after 28 days of a HFD. Increases in β cell mass during a HFD were not different when comparing values before and after a return to regular diet within the 9-, 18-, or 28-day studies. No changes were observed in apoptosis or β cell replication. Formation of intracellular markers of oxidative stress, intranuclear translocation of Nrf2, and formation of intracellular antioxidant proteins indicated the participation of HFD/oxidative stress induction of the Nrf2/antioxidant pathway. Flow cytometry-based assessment of β cell volume, morphology, and insulin-specific immunoreactivity, as well as ultrastructural analysis by transmission electron microscopy, revealed that short-term exposure to a HFD produced significant changes in β cell morphology and function that are reversible after returning to regular chow. These results suggest that a possible mechanism mediating the ability of β cells to self-repair after a short-term exposure to a HFD is the activation of the Nrf2/antioxidant pathway.

Dataset Information

Redox Balance, Antioxidant Defense, and Oxidative Damage in the Hypothalamus and Cerebral Cortex of Rats with High Fat Diet-Induced Insulin Resistance.

Publications

Redox Balance, Antioxidant Defense, and Oxidative Damage in the Hypothalamus and Cerebral Cortex of Rats with High Fat Diet-Induced Insulin Resistance.

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