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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism, by which a high-fat (HF) diet could impair glucose metabolism, is not completely understood but could be related to inflammation, lipotoxicity and oxidative stress. Lipid peroxides have been proposed as key mediators of intracellular metabolic response. The purpose of the present study was to analyse, in mice fed with a HF diet, the possible association between obesity and glucose tolerance on the one hand, and between oxidative stress and lipid peroxidation on the other hand. The present results show that a HF diet (70 % energy as fat), v. a high-carbohydrate chow diet (control), increases body weight and fat mass development, and impairs glycaemia and insulinaemia within 4 weeks. It also promotes the expression of NADPH oxidase in the liver--signing both oxidative and inflammatory stress--but decreases thiobarbituric acid-reactive substances content in the liver as well as in epididymal, subcutaneous and visceral adipose tissues. HF diet, with elevated vitamin E content, induces high concentration of alpha-tocopherol in liver and adipose tissues, which contributes to the protection against lipid peroxidation. Thus, lipid peroxidation in key organs is not necessarily related to the development of metabolic disorders associated with diabetes and obesity.
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PMID:Lipid peroxidation is not a prerequisite for the development of obesity and diabetes in high-fat-fed mice. 1916 40

Leptin, a 16-kDa cytokine produced mainly by the adipose tissue, is known to increase energy expenditure while at the same time lowering food intake by acting directly on the hypothalamus. ObRb, the leptin receptor mostly involved in intracellular signaling, is expressed in a wide range of tissues, thus allowing leptin to affect a much broader diversity of biological processes. High concentrations of leptin are encountered in patients with hyperleptinemia, a condition which very often accompanies obesity and which is a direct result of leptin resistance. In the present study, moderate and high concentrations of leptin (16 and 160 ng/ml) were mostly utilized in order to investigate the role of this cytokine in oxidative stress levels in human monocytes. Leptin was found to increase oxidative species production as measured with 2',7'-dichlorodihydrofluorescein diacetate (general marker of oxidative species, but not O2-*) and dihydroethidium (marker of O2-*). Surprisingly, it also augmented superoxide dismutase activity. Inhibition of the Na+-H+ exchanger isoform 1 (NHE1) also inhibited leptin-induced superoxide anion production but at the same time amplified leptin-induced production of other oxidative species. Signaling proteins such as phosphoinositide 3 kinase and conventional isoforms of protein kinase C (alpha-, beta(i)-, beta(ii)-), as well as NADPH oxidase, also participated in leptin signaling. Finally, leptin was found to increase glutathionylation levels of NHE1-bound heat shock protein 70 kDa (Hsp70) but not Hsp70 binding to NHE1.
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PMID:The ambiguous role of the Na+-H+ exchanger isoform 1 (NHE1) in leptin-induced oxidative stress in human monocytes. 1930 Nov 49

Diabetic nephropathy is the leading cause of renal failure in the United States. The obese Zucker rat (OZR; fa/fa) is a commonly used model of type 2 diabetes and metabolic syndrome (MetS), and of the nephropathy and renal oxidative stress commonly seen in these disorders. Heterozygous lean Zucker rats (LZRs; fa/+) are susceptible to high-fat diet (HFD)-induced obesity and MetS. The present study was designed to investigate whether 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL), a membrane-permeable radical scavenger, could alleviate the renal effects of MetS in OZR and LZR fed a HFD, which resembles the typical "Western" diet. OZR and LZR were fed a HFD (OZR-HFD and LZR-HFD) or regular diet (OZR-RD and LZR-RD) and allowed free access to drinking water or water containing 1 mmol/l TEMPOL for 10 weeks. When compared to OZR-RD animals, OZR-HFD animals exhibited significantly higher levels of total renal cortical reactive oxygen species (ROS) production, plasma lipids, insulin, C-reactive protein, blood urea nitrogen (BUN), creatinine (Cr), and urinary albumin excretion (P < 0.05); these changes were accompanied by a significant decrease in plasma high-density lipoprotein levels (P < 0.05). The mRNA expression levels of desmin, tumor necrosis factor-alpha (TNF-alpha), nuclear factor kappaB (NFkappaB), and NAD(P)H oxidase-1 (NOX-1) were significantly higher in the renal cortical tissues of OZR-HFD animals; NFkappaB p65 DNA binding activity as determined by electrophoretic mobility shift assay was also significantly higher in these animals. The same trends were noted in LZR-HFD animals. Our data demonstrate that TEMPOL may prove beneficial in treating the early stages of the nephropathy often associated with MetS.
Obesity (Silver Spring) 2009 Nov
PMID:Diet-induced renal changes in Zucker rats are ameliorated by the superoxide dismutase mimetic TEMPOL. 1942 63

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (Vo(2)). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak Vo(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.
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PMID:Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. 1961 6

We examined the effect of high-fat (HF) feeding on blood pressure (BP) regulation, including hypothalamic redox signaling, as well as the changes in diurnal patterns and responses to restraint stress. Furthermore, we investigated whether HF feeding affects catecholamine and neuropeptide Y (NPY) biosynthesis in the adrenal medulla. Male obesity-prone Sprague-Dawley rats were fed with standard rat chow or 60% HF diet for 6 months. BP and heart rate (HR) were measured by telemetry, and circadian changes as well as responses to 20 min restraint stress were analyzed. Mean arterial BP was significantly elevated in HF rats both during daytime and nighttime compared with controls, whereas HR was elevated only during the day. BP and HR increased similarly in response to stress in both experimental groups; however, post-stress recovery of BP and HR were significantly delayed in HF animals. Protein levels of angiotensin II type 1 receptor (AT(1)) and NOX2, p67(phox) and p47(phox) subunits of NADPH oxidase, as well as NADPH oxidase activity increased significantly in the hypothalamus with HF feeding, whereas levels of antioxidant enzymes and nitric oxide synthases remained unchanged. In addition, HF diet also elevated the adrenomedullary protein levels of tyrosine hydroxylase and NPY. This study shows that feeding obesity-prone Sprague-Dawley rats with a HF diet results in elevated BP and HR and delayed cardiovascular post-stress recovery, and that these changes are paralleled by increases in the expression and activity of NADPH oxidase in the hypothalamus without a compensatory increase in the antioxidant enzyme levels, possibly leading to superoxide-mediated sympathoexcitation and hypertension.
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PMID:Effect of high-fat diet feeding on hypothalamic redox signaling and central blood pressure regulation. 1971 64

Insulin resistance is associated with obesity and may be accompanied by left ventricular diastolic dysfunction and myocardial remodeling. Decreased insulin metabolic signaling and increased oxidative stress may promote these maladaptive changes. In this context, the beta-blocker nebivolol has been reported to improve insulin sensitivity, increase endothelial NO synthase activity, and reduce NADPH oxidase-induced superoxide generation. We hypothesized that nebivolol would attenuate diastolic dysfunction and myocardial remodeling by blunting myocardial oxidant stress and promoting insulin metabolic signaling in a rodent model of obesity, insulin resistance, and hypertension. Six-week-old male Zucker obese and age-matched Zucker lean rats were treated with nebivolol (10 mg x kg(-) x day(-1)) for 21 days, and myocardial function was assessed by cine MRI. Compared with untreated Zucker lean rats, untreated Zucker obese rats exhibited prolonged diastolic relaxation time (27.7+/-2.5 versus 40.9+/-2.0 ms; P<0.05) and reduced initial diastolic filling rate (6.2+/-0.5 versus 2.8+/-0.6 microL/ms; P<0.05) in conjunction with increased homeostatic model assessment of insulin resistance (7+/-2 versus 95+/-21; P<0.05), interstitial and pericapillary fibrosis, abnormal cardiomyocyte histoarchitecture, 3-nitrotyrosine, and NADPH oxidase-dependent superoxide. Nebivolol improved diastolic relaxation (32.8+/-0.7 ms; P<0.05 versus untreated Zucker obese), reduced fibrosis, and remodeling in Zucker obese rats, in concert with reductions in nitrotyrosine, NADPH oxidase-dependent superoxide, and improvements in the insulin metabolic signaling, endothelial NO synthase activation, and weight gain (381+/-7 versus 338+/-14 g; P<0.05). Results support the hypothesis that nebivolol reduces myocardial structural maladaptive changes and improves diastolic relaxation in concert with improvements in insulin sensitivity and endothelial NO synthase activation, concomitantly with reductions in oxidative stress.
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PMID:Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat. 2017 97

Although obesity-related cardiovascular disease and hypoxia are associated with erectile dysfunction, little is known about the direct effects of hypoxia on penile arteries. In the present study, the effects of acute hypoxia (Po(2) = approximately 10 Torr, 20 min) were investigated in isolated penile arteries to determine the influence of endothelium removal, nitric oxide (NO) synthase (NOS), cyclooxygenase (COX), NADPH oxidase, changes in reactive oxygen species (ROS), and a high-fat diet. Hypoxia-relaxed penile arteries contracted with phenylephrine by approximately 50%. Relaxation to hypoxia and acetylcholine was reduced by endothelium removal and by inhibition of NOS (N(omega)-nitro-l-arginine) and COX (indomethacin) but was enhanced by Tempol and by NADPH oxidase inhibition with apocynin and gp91ds-tat. Basal superoxide levels detected by lucigenin chemiluminescence were reduced by Tempol and gp91ds-tat and were enhanced by NOS blockade. Hypoxic relaxant responses were enhanced by catalase and ebselen. Exogenous peroxide evoked relaxations of penile arteries, which were partially inhibited by endothelium removal and by the inhibition of COX and extracellular signal-regulated mitogen-activated protein kinase (MAPK) but enhanced by p38 MAPK blockade. The NO-dependent component of relaxation to hypoxia was impaired in penile arteries from high-fat diet-fed, obese rats associated with increased superoxide production. Thus hypoxic relaxation of penile arteries is partially mediated by endothelial NO in a manner that is normally attenuated by endogenous ROS production. Obesity further increases superoxide production and impairs the influence of NO. Therefore, cardiovascular disease involving decreased NO bioavailability and/or enhanced ROS generation may contribute to erectile dysfunction through impairing the relaxation of penile arteries to hypoxia.
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PMID:Hypoxic relaxation of penile arteries: involvement of endothelial nitric oxide and modulation by reactive oxygen species. 2058 Oct 86

The pathogenesis of nonalcoholic steatohepatitis (NASH) is not well understood; however, the progression of fatty liver to NASH has been linked to oxidative stress and lipid peroxidation in the liver, leading to inflammation. Although the adiponectin receptor 2 (AdipoR2) has been identified as a modulator of oxidative stress and inflammation in the liver, it remains unclear whether the receptor has hepatic antioxidant and anti-inflammatory effects in NASH. In this study, we used an animal model of NASH to examine hepatic AdipoR2. Obese fa/fa Zucker rats fed a high-fat and high-cholesterol (HFC) diet spontaneously developed fatty liver with inflammation and fibrosis, characteristic of NASH, after 4, 8, or 12 weeks of HFC diet consumption. AdipoR2 expression was significantly decreased, whereas the expression of genes related to NADPH oxidase complex were increased. As a result of the decrease in AdipoR2 expression, the mRNA expression of genes located downstream of AdipoR2, i.e., Cu-Zn superoxide dismutase (Cu-Zn SOD) and Mn-SOD, also decreased. Furthermore, the expression of genes related to inflammation was increased. Increased oxidative stress and inflammation by down-regulation of AdipoR2 may contribute to the progression of NASH. Thus, the AdipoR2 might be a crucially important regulator of hepatic oxidative stress and inflammation in NASH.
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PMID:Regulation of oxidative stress and inflammation by hepatic adiponectin receptor 2 in an animal model of nonalcoholic steatohepatitis. 2060 28

We assessed the effect of epinephrine on human monocytes. Monocytes were isolated from 16 healthy obese and 10 lean healthy subjects. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. Obese subjects were subdivided into 2 sub-groups, insulin sensitive (IS) and insulin resistant (IR). Monocyte properties [attachment to laminin 1, migration through laminin 1, oxidized-low density lipoprotein (oxLDL) phagocytosis] were assessed pre- and post-stimulation in vitro with epinephrine. Experiments were repeated after incubation with a Na(+)/H( +) exchanger-1 inhibitor (NHE-1) (cariporide). Epinephrine increased monocyte attachment to laminin in lean and obese IR subjects through involvement of NHE-1, PKC, NO synthase, NADPH oxidase and actin polymerization. In contrast, epinephrine did not affect monocyte migration. Epinephrine increased oxLDL phagocytosis in all groups studied. Incubation with cariporide attenuated oxLDL phagocytosis. Epinephrine induces monocyte dysfunction which may be atherogenic.
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PMID:Effect of epinephrine and insulin resistance on human monocytes obtained from lean and obese healthy participants: a pilot study. 2147 69

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, autosomal-recessive disorder associated with several clinical features including obesity, hypertension, and cardiovascular abnormalities. BBS proteins play an important role in the function of cilia, a mechanosensory organelle in endothelial cells, but whether these proteins are directly involved in the regulation of vascular function is unclear. Here, we show that Bbs genes (1-12) are expressed in endothelial and smooth muscle cell lines and tissues enriched in endothelial (lung) and smooth muscle (stomach) cells as well as the aorta. Next, we used aortic rings to examine the vascular function of two BBS mouse models that recapitulate the human phenotype, namely Bbs2(-/-) (obese and normotensive) and Bbs6(-/-) (obese and hypertensive) mice. Interestingly, the endothelium-dependent relaxation (induced by ACh) was significantly enhanced in Bbs2(-/-) but not Bbs6(-/-) mice. In contrast, the endothelium-independent relaxation (induced by sodium nitroprusside) was unaltered in both BBS mouse models. In addition, the contractile responses to serotonin and endothelin-1 were attenuated in Bbs2(-/-) but not Bbs6(-/-) mice. Of note, the NO-producing enzymes (eNOS and iNOS) were upregulated in the aorta of Bbs2(-/-) but not Bbs6(-/-) mice. On the other hand, the expression level of membrane subunits of NADPH oxidase (p22(phox) and p47(phox)) in the aorta was decreased in Bbs2(-/-) mice but increased in Bbs6(-/-) mice. In conclusion, these data implicate Bbs genes in the regulation of vascular function and demonstrate that disrupting Bbs2 and Bbs6 genes affect differentially the vascular function.
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PMID:Contrasting vascular effects caused by loss of Bardet-Biedl syndrome genes. 2085 44


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