Oxidative Stress In Obese Mice Research Articles

WED-535 - A formulation of palmitoylethanolamide and phenolic compounds improves NAFLD-associated hepatic lipid dysmetabolism and oxidative stress in obese mice

WED-535 - A formulation of palmitoylethanolamide and phenolic compounds improves NAFLD-associated hepatic lipid dysmetabolism and oxidative stress in obese mice

Standardized Sanguisorba officinalis L. Extract Inhibits Adipogenesis and Promotes Thermogenesis via Reducing Oxidative Stress.

Obesity produces many health problems, including systemic oxidative stress. This study comprehensively investigated the effects of Sanguisorba officinalis L. extract (SO) as an antioxidant on abnormal lipid accumulation and oxidative stress in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice (n = 48). We evaluated the anti-adipogenic and antioxidant effects of SO on 3T3-L1 by cell viability, Oil red O staining, and NBT assays. The ameliorative effects of SO in HFD-induced C57BL/6J mice were investigated by measuring body weight, serum lipids, adipocyte size, hepatic steatosis, AMPK pathway-related proteins, and thermogenic factors. In addition, the effect of SO on oxidative stress in obese mice was evaluated by the activity of antioxidant enzymes and the production of lipid peroxidation products and ROS production in adipose tissue. We found that SO dose-dependently decreased lipid accumulation and ROS production in 3T3-L1 adipocytes. In C57BL/6J obese mice, SO (above 200 mg/kg) attenuated the HFD-induced gain in body weight and white adipose tissue (WAT) weight without affecting appetite. SO also decreased serum glucose, lipid, and leptin levels and attenuated adipocyte hypertrophy and hepatic steatosis. Furthermore, SO increased the expression of SOD1 and SOD2 in WAT, decreased ROS and lipid peroxides, and activated the AMPK pathway and thermogenic factors. In summary, SO reduces oxidative stress in adipose tissue by increasing antioxidant enzyme activity and improves obesity symptoms through AMPK-pathway-regulated energy metabolism and mitochondrial respiratory thermogenesis.

Endoplasmic reticulum stress increases exosome biogenesis and packaging relevant to sperm maturation in response to oxidative stress in obese mice

BackgroundMammalian sperm maturation in the epididymis is mainly modulated by exosomes that are secreted into the epididymal lumen from epididymal epithelial cells (EECs). Exposure to oxidative stress (OS) resulting from being fed a high fat diet (HFD) reduces sperm fertility, which is one of the cause inducing male infertility. Thus, we hypothesize that stress-induced changes in exosome content play a critical role in mediating this detrimental process. MethodsAn obese mouse model was established by feeding a HFD. Then oxidative stress status was measured in the mouse caput epididymis, epididymal fluid and spermatozoa. Meanwhile, epididymis-derived purified exosomes were isolated and validated. Subsequently, liquid chromatography tandem mass spectrometry (LC-MS) was used to perform proteomic analysis of purified exosomes. Gene Ontology (GO) analysis was performed along with pathway enrichment to identify differentially expressed proteins (DEPs).ResultsTwo hundred and two DEPs mostly related to endoplasmic reticulum (ER) function were identified in the exosomes separated from the epididymis of control mice and obese mice. The ER stress and CD63 (an exosome marker), both increased in the caput epididymis of obese mice. Furthermore, an in vitro study showed that palmitic acid (PA), an-oxidative stress inducer, increased exosome biogenesis and secretion in the EECs.ConclusionOxidative stress in the epididymal microenvironment induces ER stress in the EECs. This effect alters the epididymis-derived exosome content, profile and amounts of their differentially expressed ER proteins. Such changes may affect exosome biogenesis and cargo packaging, finally leading to abnormalities in sperm maturation and fertility.

Dietary tea seed saponin combined with aerobic exercise attenuated lipid metabolism and oxidative stress in mice fed a high-fat diet (HFD).

Tea seed saponins (TSS) are oleanolane-type pentacyclic triterpenoid saponin mixtures with various pharmacological effects. We aimed to explore the effects of a total of 4 weeks intragastric administration of TSS (140 mg/kg·day) combined with aerobic exercise (AE) on lipid metabolism and its associated oxidative stress in HFD-induced obese mice and to investigate the possible molecular mechanisms. TSS + AE intervention significantly reduced body weight and the adiposity index (including subcutaneous, epididymal, perirenal, and abdominal adipose) in obese mice; improved dyslipidemia by lowering serum TC, TG, and LDL-c levels; and increased HDL-c levels. TSS + AE intervention significantly improved hepatic steatosis by inhibiting lipogenetic Acc, Srebp1c, and Scd1 and upregulating lipolysis genes (Pgc1α, Pgc1β, Pparα, and Cpt1). TSS + AE intervention increased the hepatic protein expression of p-AMPK, SIRT1, and PGC-1α, as well as PPAR-γ and GLUT-4 in skeletal muscle compared with expression in the HFD group. In addition, TSS + AE also modulated oxidative stress in obese mice, which was indicated by the increased serum and liver levels of SOD, GSH, and T-AOC and decreased ROS and MDA levels. These results suggest that TSS + AE intervention can reduce fat accumulation and improve HFD-induced lipid metabolism disorders and oxidative stress. PRACTICAL APPLICATIONS: Obesity is a metabolic disease induced by excess nutritional intake and insufficient energy expenditure. Dietary modifications combined with aerobic exercise are currently an effective method for weight loss. Tea seed saponins (TSS) are a variety of biologically active oleanolane-type pentacyclic triterpenoid saponins that naturally exist in tea seeds. Few articles have focused on the effects and mechanisms of TSS combined with aerobic exercise (AE) in regulating lipid metabolism and improving oxidative damage in vivo. Using an HFD-induced obese mice model to explore the mechanism of TSS + AE in regulating lipid metabolism and its associated oxidative stress damage will help provide reliable data for the application of dietary nutrition combined with AE in anti-obesity.

Effects of aerobic exercise and dietary intervention on testicular oxidative stress in obese mice

Through aerobic exercise and diet intervention on obese mice, the effects of exercise and diet intervention on testicular oxidative stress and p38MAPK-NF-κB pathway were investigated in obese mice. Seventeen C57BL/6J mice were randomly divided into a normal diet group (ND), and 37 mice were divided into a high-fat diet group (HFD), the high-fat diet accounted for 40% of fat. After 12 weeks of feeding, 3 obesity-resistant mice were excluded from the HFD group, and the remaining 34 were successfully modeled. The mice in ND group were then divided into normal diet control group (NC, n=8) and normal diet and exercise group (NE, n=9). The mice in HFD group were divided into obese high-fat diet control group (OC, n=8), obese high-fat diet and exercise group (OE, n=9), obese normal diet group (ONC, n=8), and obese normal diet and exercise group (ONE, n=9). Each group continued to feed for 8 weeks, and the NE, OE and ONE groups performed treadmill exercise for 8 weeks at a speed of 20 m/min, 60 min/d, 6 d/week. Blood and testicular tissue samples were collected 36～40 h after the last exercise. Serum testosterone and testicular oxidative stress (MDA, T-SOD, T-AOC) levels were detected by ELISA, and testicular p38MAPK-NF-κB levels were detected by RT-PCR and Western blot. Compared with the NC group, the body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels in the OC group were increased significantly (P＜0.01), while the levels of testicular SOD, testis coefficient and blood testosterone were decreased significantly (P＜0.01); the body fat parameters of the mice in the NE group were decreased significantly (P＜0.05), and the serum level of testosterone was increased significantly (P＜0.01). Compared with the OC group, the body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels were decreased significantly in the OE group (P＜0.05 or 0.01), and the testicular SOD and blood testosterone levels were increased significantly (P＜0.01); Body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels were decreased significantly in ONC group (P＜0.01), while testicular SOD level and testis coefficient were increased significantly (P＜0.05); Body fat parameters, testicular MDA and testicular p38MAPK-NF-κB mRNA and protein levels of mice in ONE group were decreased significantly (P＜0.01), while testicular SOD, testis coefficient and blood testosterone levels were increased significantly (P＜0.01). Obesity induces oxidative stress in the testis of mice, up-regulates the level of p38MAPK-NF-κB, and reduces the level of blood testosterone; exercise, diet and exercise*diet interventions can reduce testicular oxidative stress and down-regulate testicular p38MAPK-NF-κB levels by reducing body fat.

Dietary Geranylgeraniol and Statins May Act Synergistically to Mitigate Oxidative Stress in Obese Mice

ObjectivesThis study aimed to determine the individual and combined effects of dietary geranylgeraniol (GG) and statins on oxidative stress in high-fat diet (HFD)-fed animals. MethodsFive-week-old male C57BL/6J mice were stratified by initial body weight into a 2 × 2 factorial design with four groups: HFD (60% kcal from fat), HFD + statin (120 mg/kg diet), HFD + GG (400 mg/kg diet), or HFD + GG + statin. Following 14 weeks of treatment, mice were sacrificed, and liver was collected for analysis. Protein expression of the pro-oxidant enzyme, NADPH oxidase (NOX) 4, and antioxidant enzymes, superoxide dismutase 2 (SOD2) and catalase, as well as the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were assessed by western blot. Results were analyzed by two-way ANOVA followed by Tukey-Kramer post-hoc test. ResultsWe found GG supplementation (HFD + GG group) reduced expression of NOX4 in the liver of obese mice, compared with the HFD group (0.41 ± 0.07-fold, n = 6, vs. 1.00 ± 0.24-fold, n = 6, p = 0.02). The combined, but not individual, treatment with statin and GG (HFD + GG + statin group) significantly increased the expression of SOD2 (1.68 ± 0.36-fold, n = 5, vs. 1.00 ± 0.12-fold, n = 6, p = 0.0002) and catalase (2.30 ± 0.57-fold, n = 5, vs. 1.00 ± 0.14-fold, n = 6, P < 0.0001) compared to the HFD group. Interestingly, NRF2 expression was increased only by statin treatment, without GG supplementation (HFD + GG group), (1.00 ± 0.45-fold, n = 6, vs. 2.20 ± 0.86-fold, n = 6, p = 0.03) compared to HFD. ConclusionsOral statins and dietary GG have the potential to mitigate oxidative stress individually or in a synergistic manner by attenuating NOX4 and increasing antioxidant enzymes such as SOD2 and catalase. Funding SourcesAmerican River Nutrition, LLC, Hadley, MA.

Inhibition of GCN2 alleviates hepatic steatosis and oxidative stress in obese mice: Involvement of NRF2 regulation

The development of nonalcoholic fatty liver disease (NAFLD) is associated with increased reactive oxygen species (ROS) production. Previous observations on the contradictory roles of general control nonderepressible 2 (GCN2) in regulating the hepatic redox state under different nutritional conditions prompted an investigation of the underlying mechanism by which GCN2 regulates ROS homeostasis. In the present study, GCN2 was found to interact with NRF2 and decrease NRF2 expression in a KEAP1-dependent manner. Activation of GCN2 by halofuginone treatment or leucine deprivation decreased NRF2 expression in hepatocytes by increasing GSK-3β activity. In response to oxidative stress, GCN2 repressed NRF2 transcriptional activity. Knockdown of hepatic GCN2 by tail vein injection of an AAV8-shGcn2 vector attenuated hepatic steatosis and oxidative stress in leptin-deficient (ob/ob) mice in an NRF2-dependent manner. Inhibition of GCN2 by GCN2iB also ameliorated hepatic steatosis and oxidative stress in both ob/ob mice and high fat diet-fed mice, which was associated with significant changes in lipid and amino acid metabolic pathways. Untargeted metabolomics analysis revealed that GCN2iB decreased fatty acid and sphingomyelin levels but increased aliphatic amino acid and phosphatidylcholine levels in fatty livers. Collectively, our results provided the first direct evidence that GCN2 is a novel regulator of NRF2 and that specific GCN2 inhibitors might be potential drugs for NAFLD therapy.

Kaempferide improves oxidative stress and inflammation by inhibiting the TLR4/IκBα/NF-κB pathway in obese mice.

Objective(s):Kaempferide (Ka), a major natural active component of Tagetes erecta L, has numerous pharmacological effects such as anti-obesity, anticancer, and anti-hypertension. However, there is no clear evidence that Ka is directly related to inflammation and oxidative stress in obese mice. We aimed to explore the effects of Ka on inflammation and oxidative stress and its mechanism.Materials and Methods:The obese mice were induced by a high-fat diet (HFD). The anti-obesity effect was tested by liver and body weight, liver and adiposity index, and white adipose tissue. Blood sample analysis was used to detect the hypolipidemic and hypoglycemic effects. The anti-oxidation effect was assessed using GSH, SOD, MDA, CAT, T-AOC, and other indicators. The anti-inflammatory effect was assessed using TNF-α, MCP-1, and Adiponectin. Western blot and Real-Time PCR were used to evaluate the related signaling pathways.Results:Obesity, glycolipid metabolism disorder, inflammation, and oxidative stress developed in HFD mice. These changes can be effectively alleviated by Ka treatment for 16 weeks. Further studies have suggested that these beneficial effects of Ka may be associated with inhibition of the TLR4/IκBα/NF-κB signaling pathways. Conclusion:Ka possesses important anti-obesity, hypoglycemic, and hypolipidemic effects. The mechanism may be causally associated with the TLR4/IκBα/NF-κB signaling pathway, which improves inflammation and oxidative stress.

Effects of Lycium barbarum Polysaccharide on Endoplasmic Reticulum Stress and Oxidative Stress in Obese Mice.

BackgroundThe incidence of obesity-associated decline in male fertility has increased over the years. Lycium barbarum polysaccharide (LBP), a natural plant polysaccharide extracted from the Chinese herb L. barbarum has shown promising therapeutic effects in overcoming the same.AimThis study aimed to investigate the protective effect of LBP on the testes of obese mice.MethodsFollowing administration of LBP to high-fat diet-induced obese mice for 35 days, serum, sperm, and testis samples were obtained for subsequent experiments. Biochemical analysis and sex hormone content determination were performed to observe changes in glycolipid metabolism and testosterone levels, respectively, in the blood. Hematoxylin and eosin staining were carried out to assess the pathological changes in the testicular tissue. Oxidative stress levels were detected using enzyme-linked immunosorbent assay and expression levels of endoplasmic reticulum stress markers were determined using western blot in the testicular tissue.ResultsOur results suggested that LBP reduced glucose levels and insulin resistance, increased testosterone levels and insulin sensitivity, and decreased testicular oxidative stress and pathological damage in obese mice. In addition, LBP down-regulated the expression of p-eIF2α, GRP78, and CHOP in the testicular tissues of obese mice.ConclusionOur results show that LBP is a potential novel drug for preventing male infertility caused by obesity.

Resveratrol Protects Against Renal Damage via Attenuation of Inflammation and Oxidative Stress in High-Fat-Diet-Induced Obese Mice.

Oxidative stress and inflammation play an important role in the chronic kidney disease associated with obesity. Resveratrol (RSV) has been reported to exhibit a wide range of biological activities including antioxidant and anti-inflammatory properties. The objective of the present study was to investigate the effects of RSV on renal inflammation and oxidative stress in obese mice induced by high-fat diet. Male C57BL/6 mice were induced to have nephropathy associated obesity by high-fat diet for 12weeks. After 8weeks of feeding, oral supplementation with 100mg RSV/kg body weight/day was applied with the high-fat-diet feeding for another 4weeks. The results showed that RSV treatment protected against renal damage induced by high-fat diet, as evidenced by the decreased serum creatinine and urea nitrogen levels, alleviation of glomerular damage, and tubular vacuolization. In addition, RSV enhanced the antioxidant enzyme activity; improved the expression of genes related to inflammation; and decreased the malondialdehyde, tumor necrosis factor-α, and interleukin-6 concentrations in the kidney of high-fat-diet mice. In conclusion, RSV could alleviate renal damage in obese mice induced by high-fat diet via suppressing inflammation and oxidative stress.

JNK1 ablation in mice confers long‐term metabolic protection from diet‐induced obesity at the cost of moderate skin oxidative damage

Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.-Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage.

M1 Polarization Bias and Subsequent Nonalcoholic Steatohepatitis Progression Is Attenuated by Nitric Oxide Donor DETA NONOate via Inhibition of CYP2E1-Induced Oxidative Stress in Obese Mice

Activation of M1 macrophages in nonalcoholic steatohepatitis (NASH) is produced by several external or endogenous factors: inflammatory stimuli, oxidative stress, and cytokines are known. However, any direct role of oxidative stress in causing M1 polarization in NASH has been unclear. We hypothesized that CYP2E1-mediated oxidative stress causes M1 polarization in experimental NASH, and that nitric oxide (NO) donor administration inhibits CYP2E1-mediated inflammation with concomitant attenuation of M1 polarization. Because CYP2E1 takes center stage in these studies, we used a toxin model of NASH that uses a ligand and a substrate of CYP2E1 for inducing NASH. Subsequently, we used a methionine and choline-deficient diet-induced rodent NASH model where the role of CYP2E1 in disease progression has been shown. Our results show that CYP2E1 causes M1 polarization bias, which includes a significant increase in interleukin-1β (IL-1β) and IL-12 in both models of NASH, whereas CYP2E1-null mice or diallyl sulfide administration prevented it. Administration of gadolinium chloride (GdCl3), a macrophage toxin, attenuated both the initial M1 response and the subsequent M2 response, showing that the observed increase in cytokine levels is primarily from macrophages. Based on the evidence of an adaptive NO increase, the NO donor administration in vivo that mechanistically inhibited CYP2E1 catalyzed the oxidative stress during the entire study in NASH-abrogated M1 polarization and NASH progression. The results obtained show the association of CYP2E1 in M1 polarization, and that inhibition of CYP2E1 catalyzed oxidative stress by an NO donor (DETA NONOate [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate]) can be a promising therapeutic strategy in NASH.

Renin–angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ- db/db obese mice

Obesity-related metabolic abnormalities, including chronic inflammation and oxidative stress, increase the risk of colorectal cancer. Dysregulation of the renin–angiotensin system (RAS) also plays a critical role in obesity-related metabolic disorders and in several types of carcinogenesis. In the present study, we examined the effects of an angiotensin-converting enzyme (ACE) inhibitor and angiotensin-II type 1 receptor blocker (ARB), both of which inhibit the RAS, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ- db/db ( db/db) obese mice. Male db/db mice were given 4 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then, they received drinking water containing captopril (ACE inhibitor, 5 mg/kg/day) or telmisartan (ARB, 5 mg/kg/day) for 7 weeks. At sacrifice, administration of either captopril or telmisartan significantly reduced the total number of colonic premalignant lesions, i.e., aberrant crypt foci and β-catenin accumulated crypts, compared to that observed in the control group. The expression levels of TNF-α mRNA in the colonic mucosa of AOM-treated db/db mice were decreased by captopril and telmisartan. Captopril lowered the expression levels of TNF-α, IL-1β, IL-6, and PAI-1 mRNAs, while telmisartan lowered the expression levels of COX-2, IL-1β, IL-6, and PAI-1 mRNAs in the white adipose tissues of these mice. In addition, these agents significantly reduced the levels of urinary 8-OHdG, a surrogate marker of oxidative damage to DNA, in the experimental mice. These findings suggested that both ACE inhibitor and ARB suppress chemically-induced colon carcinogenesis by attenuating chronic inflammation and reducing oxidative stress in obese mice. Therefore, targeting dysregulation of the RAS might be an effective strategy for chemoprevention of colorectal carcinogenesis in obese individuals.

Alcohol increases tumor necrosis factor α and decreases nuclear factor‐κb to activate hepatic apoptosis in genetically obese mice†

Both obesity and alcohol can cause oxidative stress, cytokine induction, and steatohepatitis. To determine the consequences of their combination, we compared the hepatic effects of moderate ethanol binges in lean and obese ob/ob mice. Mice received water or ethanol (2.5 g/kg) by gastric intubation daily for 4 days, and were killed 2 hours after the last administration. Some obese mice also received pentoxifylline, an inhibitor of tumor necrosis factor-alpha (TNF-alpha) production, before each ethanol administration. In lean mice, these moderate ethanol doses did not increase plasma TNF-alpha and hepatic caspase-3 activity, but triggered some apoptotic hepatocytes. Naive ob/ob mice had a few necrotic and apoptotic hepatocytes, but exhibited little oxidative stress, possibly because of adaptive increases in manganese superoxide dismutase, heat shock protein 70 (Hsp70), mitochondrial cytochrome c, and mitochondrial DNA. Alcohol administration to ob/ob mice did not increase oxidative stress despite increased CYP2E1, but increased plasma TNF-alpha, further increased Hsp70, and profoundly decreased p65 nuclear factor kappaB (NF-kappaB) protein and DNA-binding activity in nuclear extracts. Caspase-3 was activated, and more apoptotic hepatocytes were found in intoxicated obese mice than naive obese mice. In intoxicated obese mice, pentoxifylline fully prevented the increase in plasma TNF-alpha the decrease in nuclear NF-kappaB activity, and the increase in hepatic caspase-3, and it also decreased hepatic triglycerides. In conclusion, obese mice develop adaptations that may limit oxidative stress. Moderate ethanol intoxication does not increase oxidative stress in obese mice, but increases TNF-alpha and also decreases nuclear NF-kappaB activity, thus unleashing the apoptotic effects of TNF-alpha.