Obesity-associated Oxidative Stress Research Articles

Rosehip Extract Decreases Reactive Oxygen Species Production and Lipid Accumulation in Hypertrophic 3T3-L1 Adipocytes with the Modulation of Inflammatory State.

Rosa canina L. (rosehip) is used worldwide in traditional medicine as a plant with medicinal properties. However, its anti-obesity effects are not fully explained on a transcriptional level. In the present work, the 3T3-L preadipocytes were utilized to explore the impact of R. canina fruit extract (RCE) on the cellular and molecular pathways involved in adipocyte hypertrophy. Obtained results showed the ability of RCE to reduce lipid overloads in hypertrophic adipocytes associated with the down-regulation of mRNA expressions of adipogenic transcription factors such as PPARγ, C/EBPα, and SREBP-1c as well as genes involved in lipid biosyntheses such as FAS, LPL, and aP2. Moreover, obesity-associated oxidative stress (antioxidant enzyme activities and ROS generation) and inflammation were ameliorated in RCE-treated hypertrophic adipocytes. The mRNA and protein levels of adipokines such as leptin, resistin, and adiponectin were restored to more favorable levels. Rosa canina fruit might be a valuable source of phytochemicals in preventing obesity and obesity-related metabolic complications.

Very low-density lipoprotein receptor mediates triglyceride-rich lipoprotein-induced oxidative stress and insulin resistance.

Obesity is associated with excess lipid deposition in nonadipose tissues, leading to increased oxidative stress and insulin resistance. Very low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity-associated oxidative stress and insulin resistance is unclear. Here, we used lean (wild type), genetically obese leptin-deficient (ob/ob), and leptin-VLDLR double-null (ob/ob-VLDLR-/-) mice to determine the impact of VLDLR deficiency on obesity-induced oxidative stress and insulin resistance in the heart. Although insulin sensitivity and glucose uptake were reduced in the hearts of ob/ob mice, VLDLR expression was upregulated and was associated with increased VLDL uptake and excess lipid deposition. This was accompanied by an upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in ob/ob mice had reduced VLDL uptake and prevented excess lipid deposition in the heart, in addition to a reduction of superoxide overproduction and the normalization of insulin sensitivity and glucose uptake. In isolated cardiomyocytes, VLDLR deficiency had prevented VLDL-mediated induction of Nox activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. Our findings indicate that VLDLR deficiency prevents excess lipid accumulation and moderates oxidative stress and insulin resistance in the hearts of obese mice. This effect is linked to the active role of VLDLR in VLDL uptake, which triggers a cascade of events leading to increased Nox activity, superoxide overproduction, and insulin resistance.NEW & NOTEWORTHY Obesity is associated with excess lipid deposition in muscles, which is considered as a leading cause of metabolic dysfunction and oxidative stress. Cellular uptake of lipids is regulated by several membrane receptors, among which is the very low-density lipoprotein receptor (VLDLR). This article provides information on the role of VLDLR in cardiac muscle and how its expression regulates insulin resistance and oxidative stress in the obese mouse model.

Testosterone Contributes to Vascular Dysfunction in Young Mice Fed a High Fat Diet by Promoting Nuclear Factor E2-Related Factor 2 Downregulation and Oxidative Stress.

Obesity, an important risk factor for cardiovascular disease, promotes vascular oxidative stress. Considering that free testosterone levels remain within the reference range, especially in obese young men and that testosterone stimulates reactive oxygen species (ROS) generation, we sought to investigate whether testosterone interferes with obesity-associated oxidative stress and vascular dysfunction in male mice. We hypothesized that testosterone favors ROS accumulation and vascular dysfunction in high fat diet (HFD)-fed obese mice. We also questioned whether testosterone downregulates the nuclear factor E2–related factor 2 (Nrf2), one of the major cellular defense mechanisms against oxidative stimuli. Male C57Bl/6J mice were submitted to orchiectomy or sham-operation. Mice received either a control diet (CD) or HFD for 18 weeks. Vascular function was assessed in thoracic aortic rings and molecular mechanisms by which testosterone contributes to vascular dysfunction were determined. HFD reduced acetylcholine-induced vasodilation and increased vascular ROS generation in sham mice. Castration prevented these effects. Treatment of castrated mice fed either the CD or HFD with testosterone propionate decreased acetylcholine vasodilation. HFD decreased Nrf2 nuclear accumulation, events linked to decreased mRNA expression and activity of Nrf2-regulated enzymes (catalase, heme oxygenase-1, peroxiredoxin, and thioredoxin). These events were prevented in HFD-fed castrated mice. Bardoxolone, a Nrf2 activator, increased nuclear accumulation of Nrf2, decreased ROS generation and improved acetylcholine vasodilation in HFD-fed sham mice. In vitro, testosterone increased ROS generation and decreased Nrf2 nuclear accumulation. These effects were prevented in the presence of an androgen receptor antagonist, an inhibitor of gene transcription and an inhibitor of the pro-oxidant enzyme NOX-1. These results indicate that testosterone downregulates Nrf2, leading to oxidative stress and vascular dysfunction in HFD-fed obese young mice.

Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress.

Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.

Metabolic Stress Alters Antioxidant Systems, Suppresses the Adiponectin Receptor 1 and Induces Alzheimer's Like Pathology in Mice Brain.

Oxidative stress and insulin resistance play major roles in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). A high-fat diet induces obesity-associated oxidative stress, neuronal insulin resistance, microglial activation, and neuroinflammation, which are considered important risk factors for neurodegeneration. Obesity-related metabolic dysfunction is a risk factor for cognitive decline. The present study aimed to elucidate whether chronic consumption of a high-fat diet (HFD; 24 weeks) can induce insulin resistance, neuroinflammation, and amyloid beta (Aβ) deposition in mouse brains. Male C57BL/6N mice were used for a high-fat diet (HFD)-induced pre-clinical model of obesity. The protein expression levels were examined via Western blot, immunofluorescence, and the behavior analysis was performed using the Morris water maze test. To obtain metabolic parameters, insulin sensitivity and glucose tolerance tests were performed. We found that metabolic perturbations from the chronic consumption of HFD elevated neuronal oxidative stress and insulin resistance through adiponectin receptor (AdipoR1) suppression in HFD-fed mice. Similarly, our in vitro results also indicated that knockdown of AdipoR1 in the embryonic mouse hippocampal cell line mHippoE-14 leads to increased oxidative stress in neurons. In addition, HFD markedly increased neuroinflammatory markers’ glial activation in the cortex and hippocampus regions of HFD mouse brains. More importantly, we observed that AdipoR1 suppression increased the amyloidogenic pathway both in vivo and in vitro. Furthermore, deregulated synaptic proteins and behavioral deficits were observed in the HFD mouse brains. Taken together, our findings suggest that excessive consumption of an HFD has a profound impact on brain function, which involves the acceleration of cognitive impairment due to increased obesity-associated oxidative stress, insulin resistance, and neuroinflammation, which ultimately may cause early onset of Alzheimer’s pathology via the suppression of AdipoR1 signaling in the brain.

Donepezil Attenuates Obesity-Associated Oxidative Stress and Central Inflammation and Improves Memory Deficit in Mice Fed a High-Fat Diet

Background/Aims: Obesity is associated with chronic inflammation and cognitive decline, and is considered a major risk factor for neurodegeneration. Meanwhile, neuroinflammation is important in the pathogenesis and progression of neurodegenerative diseases. Methods:In this study, we tested the hypothesis that donepezil would attenuate central inflammation and oxidative damage and improve memory deficit in high-fat diet (HFD)-fed mice. After 16 weeks on a HFD, C57BL/6J mice were given either donepezil (3 mg/kg, i.p.) or saline for 4 weeks in parallel to a control diet (CD) group. Thereafter, the step-through test was used to assess learning and memory function. Results: In the brain of HFD-fed mice, levels of the proinflammatory cytokines interleukin 16 and tumor necrosis factor α were reduced by donepezil treatment. Similarly, HFD-induced protein levels of advanced glycation end-products and oxidative stress in the brain were significantly decreased by donepezil treatment. Conclusion: Our results indicate that donepezil may reverse obesity-related central inflammation and oxidative damage and improve memory deficit in HFD-fed mice.

Marjoram and sage oils protect against testicular apoptosis, suppressed Ki‐67 expression and cell cycle arrest as a therapy for male infertility in the obese rats

Alterations in testicular apoptosis, cell cycle progression and proliferation rate in dietary-induced obese male rats and role of oral administration of marjoram (0.16ml/kg BW) and sage (0.05ml/kg BW) oils were evaluated. Results showed increased body weight, serum leptin, testicular lipid peroxidation, protein oxidation and nitric oxide, with reduction in serum testosterone, sperm count and endogenous enzymatic and non-enzymatic antioxidants in testis of the obese rats. Flow cytometry results revealed increased number of annexin-V (+ve) cells with activation of apoptotic proteins (Bax, caspase-3) and reduction of anti-apoptotic Bcl-2. Cell cycle arrest at phases S and G2/M with decline in expression of Bcl-2 and germ cell proliferation marker ki-67 was also validated, indicating lowered spermatogenesis in the obese rats. Supplementation of marjoram or sage oils displayed normalized body weight, sperm count, germ cells apoptosis and proliferation, suggesting the two oils as a new therapeutic approach against obesity promoted male infertility. PRACTICAL APPLICATIONS: Obese men have a greater chance of fertility problems compared to those with normal weight. Obesity-associated oxidative stress and free radicals production have shown to adversely affect sperm quality with activation of pro-apoptotic pathways, allowing germ cell death. Marjoram and sage essential oils are now being widely studied due to their antioxidant and radical scavenging properties. Our findings indicated effectiveness of the two oils for combating body weight gain, testicular oxidative stress, and apoptosis, which seemed to aid in increasing sperm count. The outcomes of this study may help scientists to formulate novel medications for improving fertility problems in men.

Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes

White adipose tissue (WAT) is not only the main tissue for energy storage but also an endocrine organ that secretes adipokines. Obesity is the most common metabolic disorder and is related to alterations in WAT characteristics, such as chronic inflammation and increasing oxidative stress. WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT-type ubiquitin E3 ligase that has been implicated in various pathologies. In the present study, we found that WWP1 was upregulated in obese WAT in a p53-dependent manner. To investigate the functions of WWP1 in adipocytes, a proteome analysis of WWP1 overexpression (OE) and knockdown (KD) 3T3-L1 cells was performed. This analysis showed a positive correlation between WWP1 expression and the abundance of several antioxidative proteins. Thus, we measured reactive oxygen species (ROS) in WWP1 OE and KD cells. Consistent with the proteome results, WWP1 OE reduced ROS levels, whereas KD increased them. These findings indicate that WWP1 is an obesity-inducible E3 ubiquitin ligase that can protect against obesity-associated oxidative stress in WAT.

Normalization of adiponectin concentrations by leptin replacement in ob/ob mice is accompanied by reductions in systemic oxidative stress and inflammation

The circulating concentrations of adiponectin, an antidiabetic adipokine, have been shown to be reduced in obesity, in relation to an increase in inflammation. The aim of the present work was to assess the effect of leptin replacement on adiponectin levels and expression as well as on markers of oxidative stress and inflammation in leptin-deficient ob/ob mice. Twelve-week-old male mice (n = 7–10 per group) were treated with either saline (wild type and ob/ob mice) or leptin (ob/ob mice) for 18 days. A third group of ob/ob mice was treated with saline and pair-fed to the amount of food consumed by the leptin-treated group. Leptin replacement restored values of adiponectin (P < 0.001), reduced circulating 8-isoprostane and serum amyloid A (SAA) levels (P < 0.05 for both), and significantly downregulated the increased gene expression of osteopontin (Spp1, P < 0.05), Saa3 (P < 0.05), Cd68 (P < 0.01), Il6 (P < 0.01) and NADPH oxidase (Nox1 and Nox2, P < 0.01) in the perirenal WAT and Spp1 (P < 0.05) in the liver of ob/ob mice. In cultured adipocytes from ob/ob mice, leptin increased (P < 0.05) the mRNA expression and secretion of adiponectin. We concluded that circulating concentrations of adiponectin are positively regulated by leptin and ameliorate obesity-associated oxidative stress and inflammation in mice.

Myricetin protects against diet-induced obesity and ameliorates oxidative stress in C57BL/6 mice.

Myricetin is a naturally occurring antioxidant commonly found in various plants. However, little information is available with respect to its direct anti-obesity effects. This study was undertaken to investigate the effect of myricetin on high-fat diet (HFD)-induced obesity in C57BL/6 mice. Administration of myricetin dramatically reduced the body weight of diet-induced obese mice compared with solely HFD-induced mice. Several parameters related to obesity including serum glucose, triglyceride, and cholesterol were significantly decreased in myricetin-treated mice. Moreover, obesity-associated oxidative stress (glutathione peroxidase (GPX) activity, total antioxidant capacity (T-AOC), and malondialdehyde (MDA)) and inflammation (tumor necrosis factor-α (TNF-α)) were ameliorated in myricetin-treated mice. Further investigation revealed that the protective effect of myricetin against HFD-induced obesity in mice appeared to be partially mediated through the down-regulation of mRNA expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), and lipogenic transcription factor sterol regulatory element-binding protein 1c (SREBP-1c). Consumption of myricetin may help to prevent obesity and obesity-related metabolic complications.

Cluster Differentiating 36 (CD36) Deficiency Attenuates Obesity-Associated Oxidative Stress in the Heart.

RationaleObesity is often associated with a state of oxidative stress and increased lipid deposition in the heart. More importantly, obesity increases lipid influx into the heart and induces excessive production of reactive oxygen species (ROS) leading to cell toxicity and metabolic dysfunction. Cluster differentiating 36 (CD36) protein is highly expressed in the heart and regulates lipid utilization but its role in obesity-associated oxidative stress is still not clear.ObjectiveThe aim of this study was to determine the impact of CD36 deficiency on cardiac steatosis, oxidative stress and lipotoxicity associated with obesity.Methods and ResultsStudies were conducted in control (Lean), obese leptin-deficient (Lepob/ob) and leptin-CD36 double null (Lepob/obCD36-/-) mice. Compared to lean mice, cardiac steatosis, and fatty acid (FA) uptake and oxidation were increased in Lepob/ob mice, while glucose uptake and oxidation was reduced. Moreover, insulin resistance, oxidative stress markers and NADPH oxidase-dependent ROS production were markedly enhanced. This was associated with the induction of NADPH oxidase expression, and increased membrane-associated p47phox, p67phox and protein kinase C. Silencing CD36 in Lepob/ob mice prevented cardiac steatosis, increased insulin sensitivity and glucose utilization, but reduced FA uptake and oxidation. Moreover, CD36 deficiency reduced NADPH oxidase activity and decreased NADPH oxidase-dependent ROS production. In isolated cardiomyocytes, CD36 deficiency reduced palmitate-induced ROS production and normalized NADPH oxidase activity.ConclusionsCD36 deficiency prevented obesity-associated cardiac steatosis and insulin resistance, and reduced NADPH oxidase-dependent ROS production. The study demonstrates that CD36 regulates NADPH oxidase activity and mediates FA-induced oxidative stress.

Abstract 326: Cd36 Deficiency Reduces Obesity-associated Inflammation And Oxidative Stress In Heart

OBJECTIVE: Obesity is often associated with diabetes and cardiovascular diseases (CVD). Mounting evidence shows that diabetes is associated with structural and functional changes in the heart. CD36 protein is highly expressed in heart and regulates lipid utilization in cardiacmyocytes. In this paper, we investigated the impact of CD36 expression on obesity-associated inflammation and oxidative stress in heart. METHODS: Studies were conducted in control lean (WT), obese leptin deficient (Lep Ob/Ob ) and leptin deficient-CD36 null (Lep Ob/Ob -CD36 -/- ) mice. To examine obesity-associated insulin resistance, glucose uptake and insulin signaling were examined in adult mouse hearts. Presence of macrophages in heart was examined with immunohistochemisty. Oxidative stress makers and activity of anti-oxidant enzymes were measured in hearts. To evaluate substrate utilization, glucose and fatty acid oxidation was tested in primary cultures of ventricular myocytes. Finally, the activity of pro-inflammatory kinases p38 mitogen-activated protein kinases (p38-MAPK), c-Jun NH2-terminal kinases (JNK) were examined in cardiacmyocytes challenged with palmitate. RESULTS: In Lep Ob/Ob , glucose uptake and oxidation in heart was lower than lean WT mice, while cardiac FA oxidation was strongly higher. Silencing CD36 in Lep Ob/Ob mouse markedly improved insulin sensitivity and glucose uptake in heart, but resulted in marked reduction of FA oxidation. Immunostaining of heart sections with macrophage specific antibody F4/80 showed that macrophage content was higher in myocardium of Lep Ob/Ob mice than Lep Ob/Ob -CD36 -/- mice. Moreover, oxidative stress markers, isoprostanes and reactive oxygen species, and expression of pro-inflammatory cytokines were higher in hearts of Lep Ob/Ob than Lep Ob/Ob -CD36-/- mice, although the activities of anti-oxidant enzymes were comparable. Chronic overload of Lep Ob/Ob cardiac myocyte with palmitate strongly induced the activity of JNK and p38-MAPK, but was less effective in Lep Ob/Ob -CD36 -/- cardiac myocytes. CONCLUSIONS: These results show that CD36 deficiency induced a significant reduction of obesity-associated oxidative stress and inflammation in heart in parallel to a drop in fatty acid oxidation.

Oxidative stress and metabolic pathologies: from an adipocentric point of view.

Oxidative stress plays a pathological role in the development of various diseases including diabetes, atherosclerosis, or cancer. Systemic oxidative stress results from an imbalance between oxidants derivatives production and antioxidants defenses. Reactive oxygen species (ROS) are generally considered to be detrimental for health. However, evidences have been provided that they can act as second messengers in adaptative responses to stress. Obesity represents a major risk factor for deleterious associated pathologies such as type 2 diabetes, liver, and coronary heart diseases. Many evidences regarding obesity-induced oxidative stress accumulated over the past few years based on established correlations of biomarkers or end-products of free-radical-mediated oxidative stress with body mass index. The hypothesis that oxidative stress plays a significant role in the development of metabolic disorders, especially insulin-resistance state, is supported by several studies where treatments reducing ROS production reverse metabolic alterations, notably through improvement of insulin sensitivity, hyperlipidemia, or hepatic steatosis. In this review, we will develop the mechanistic links between oxidative stress generated by adipose tissue in the context of obesity and its impact on metabolic complications development. We will also attempt to discuss potential therapeutic approaches targeting obesity-associated oxidative stress in order to prevent associated-metabolic complications.

Obesity-Associated Oxidative Stress: Strategies Finalized to Improve Redox State

Obesity represents a major risk factor for a plethora of severe diseases, including diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and cancer. It is often accompanied by an increased risk of mortality and, in the case of non-fatal health problems, the quality of life is impaired because of associated conditions, including sleep apnea, respiratory problems, osteoarthritis, and infertility. Recent evidence suggests that oxidative stress may be the mechanistic link between obesity and related complications. In obese patients, antioxidant defenses are lower than normal weight counterparts and their levels inversely correlate with central adiposity; obesity is also characterized by enhanced levels of reactive oxygen or nitrogen species. Inadequacy of antioxidant defenses probably relies on different factors: obese individuals may have a lower intake of antioxidant- and phytochemical-rich foods, such as fruits, vegetables, and legumes; otherwise, consumption of antioxidant nutrients is normal, but obese individuals may have an increased utilization of these molecules, likewise to that reported in diabetic patients and smokers. Also inadequate physical activity may account for a decreased antioxidant state. In this review, we describe current concepts in the meaning of obesity as a state of chronic oxidative stress and the potential interventions to improve redox balance.

Brown adipose tissue redox status in response to dietary-induced obesity-associated oxidative stress in male and female rats

Obesity is linked to systemic oxidative stress and, although brown adipose tissue (BAT) plays a crucial role in energy balance, BAT redox status effects on obesity have not been studied previously. Female rats exhibit a greater BAT thermogenic capacity, attributed to enhanced mitochondrial differentiation, than males. The aim of this study was to investigate whether the mitochondrial sexual dimorphism is related to differences in BAT redox status and to assess its role in the regulation of body weight gain in response to chronic high fat diet (HFD) feeding. Ten-week-old Wistar rats of both genders were fed a pelleted control diet or HFD for 26 weeks. Although mitochondria of female rats produced higher levels of hydrogen peroxide than those of males, females exhibited lower oxidative damage, attributed to greater glutathione peroxidase activity and higher glutathione content. In response to HFD, body weight increased markedly in females, but oxidative capacity increased only in males, thus maintaining improved BAT redox status compared with females. In conclusion, the sexual dimorphism in BAT redox status found in control animals is attenuated by the HFD. The enhanced oxidative capacity of HFD males can be related to their greater resistance to body weight gain.

New evaluations of redox regulating system in adipose tissue of obesity

During the past several decades, the incidence of obesity has significantly increased worldwide. Enormous efforts have been devoted to understanding the molecular mechanisms underlying obesity and its related metabolic disorders such as type 2 diabetes, cardiovascular disease, atherosclerosis, and hypertension. It is now well-established that altered adipocyte metabolism in obese patients is closely associated with the induction of various metabolic stresses including hyperglycemia, hyperlipidemia, hyperinsulinemia, and chronic inflammation. However, the cellular factor(s) which sense metabolic changes and/or initiate the pathological progression of obesity-induced metabolic disorders remain to be elucidated. In this review, we will discuss the possible roles of cellular NADP(+)/NADPH, which function as redox potential regulators, in the induction of obesity-associated oxidative stress, chronic inflammation, and insulin resistance and suggest G6PD, a NADPH-generating enzyme, as a novel target for treating metabolic disorders.