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

Mateusz Maciejczyk,Ewa Żebrowska,Anna Zalewska,Adrian Chabowski

doi:10.1155/2018/6940515

Mateusz Maciejczyk, Ewa Żebrowska + Show 2 more

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https://doi.org/10.1155/2018/6940515

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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.

Highlights

Type 2 diabetes (T2DM, OMIM #125853) is one of the most common metabolic disorders referred to as “the epidemic of the 21st century” [1, 2]
The increase of free fatty acids in plasma (+119%) of high fat diet (HFD)-fed rats led to insulin resistance as fasting glucose and insulin levels as well as the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly higher (+70%, 12 times and 15 times, respectively) (Table 1)
We have demonstrated that chronic administration of HFD induces IR, which may be responsible for the redox imbalance, alternations in enzymatic and nonenzymatic brain antioxidants, and enhanced oxidative damage to the rats’ cerebral cortex and hypothalamus

Summary

Introduction

Type 2 diabetes (T2DM, OMIM #125853) is one of the most common metabolic disorders referred to as “the epidemic of the 21st century” [1, 2]. The pathogenesis of T2DM involves two basic pathological defects: impaired insulin secretion and insulin resistance (IR), which may be defined as reduction or lack of insulin sensitivity to the target tissues, such as adipose tissue, muscles, and the liver [3]. Excessive accumulation of FFA in cells inhibits glucose uptake, which is responsible for the malfunctioning of signal transduction pathways regulated by diacylglycerol (DAG) [3] In these conditions, the increased activity of stress-induced serine-threonine kinases (e.g., JNK kinase) leads to phosphorylation of serine residues in the insulin receptor substrate (IRS) which blocks the effect of the insulin signaling pathway [4, 5].

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