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Query: UMLS:C0028754 (obesity)
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The objective of this paper is to evaluate adaptations in hepatic mitochondrial protein mass, function and efficiency in a rat model of high-fat diet-induced obesity and insulin resistance that displays several correlates to human obesity. Adult male rats were fed a high-fat diet for 7 weeks. Mitochondrial state 3 and state 4 respiratory capacities were measured in liver homogenate and isolated mitochondria by using nicotinamide adenine dinucleotide, flavin adenine dinucleotide and lipid substrates. Mitochondrial efficiency was evaluated by measuring proton leak kinetics. Mitochondrial mass was assessed by ultrastructural observations and citrate synthase (CS) activity measurements. Mitochondrial oxidative damage and antioxidant defence were also considered by measuring lipid peroxidation, aconitase and superoxide dismutase (SOD) specific activity. Whole body metabolic characteristics were obtained by measuring 24-h oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (RQ) and nonprotein respiratory quotient (NPRQ), using indirect calorimetry with urinary nitrogen analysis. Whole body glucose homeostasis was assessed by measuring plasma insulin and glucose levels after a glucose load. Adult rats fed a high-fat diet for 7 weeks, exhibit not only obesity, insulin resistance and hepatic steatosis, but also reduced respiratory capacity and increased oxidative stress in liver mitochondria. Our present results indicate that alterations in the mitochondrial compartment induced by a high-fat diet are associated with the development of insulin resistance and ectopic fat storage in the liver. Our results thus fit in with the emerging idea that mitochondrial dysfunction can led to the development of metabolic diseases, such as obesity, type 2 diabetes mellitus and nonalcoholic steatohepatitis.
Obesity (Silver Spring) 2008 May
PMID:Alterations in hepatic mitochondrial compartment in a model of obesity and insulin resistance. 1827 91

Factors responsible for presbyacusis include physiological ageing processes as well as endogenous or exogenous causes. In the industrial countries, two main exogenous causes are exposure to loud noise and obesity. Pathomechanisms contributing to presbyacusis are hypoxia/ischemia, reactive species formation and oxidative stress, apoptotic and necrotic death of hair cells and spiral ganglion cells as well as inherited and acquired mutations in the mitochondrial DNA. Important for the successful treatment of presbyacusis is a timely fitting of hearing aids on both ears to improve communication and provide the auditory system with acoustic information. Using the hearing aids will also elevate the detection threshold of an existing tinnitus signal. At present, several therapeutic strategies based on pharmacological intervention are under discussion. The application of antioxidants or caloric restriction are considered to prevent or reduce oxidative stress-induced damage. Animal experiments evidenced that superoxide dismutase 2 (SOD2) strongly decreases in age; thus, a further approach may be the overexpression or modulation of the SOD2 within the cochlea. Adenoviral-mediated gene transfer technology would be a tempting approach to address this type of therapy. Finally, hair cell regeneration could be a possible treatment of presbyacusis in the future.
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PMID:[Pathogenesis and treatment of presbyacusis. Current status and future perspectives]. 1833 47

To understand whether oxidants contribute to the initiation and/or promulgation toward aging, the present study has been undertaken on 220 healthy male volunteers aged 20-80 years selected from the defined electoral area (suburbs of Tirupati, Andhra Pradesh, India) to evaluate the concentrations of free radicals (superoxide anion, hydrogen peroxide), lymphocyte antioxidant enzymes (glutathione S-transferase, superoxide dismutase, catalase), and DNA damage in relation to obesity and smoking (lifestyles). A two fold increase of lymphocyte free radical generation (DNA damage) was observed in older age groups with a reduced antioxidant potential, forming a link between cigarette smoking and oxidative stress represented by an antioxidant imbalance. Body mass index had a positive relationship with oxidative stress, but antioxidant levels did not vary with body mass index. The findings conclude that free radical-mediated oxidative stress and DNA damage accelerate with lifestyle variations under reduced antioxidant potential.
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PMID:Age-related correlation between antioxidant enzymes and DNA damage with smoking and body mass index. 1842 59

Insulin resistance and hyperinsulinemia are commonly present in obesity and pre-diabetes, and hyperinsulinemia is both a marker and a cause for insulin resistance. However, the molecular link between hyperinsulinemia and insulin resistance remains elusive. The present study examined the effect of chronic insulin treatment on the reactive oxygen species (ROS) production, insulin signalling and insulin-stimulated glucose uptake in 3T3-L1 adipocytes. The results showed that chronic insulin treatment significantly increased the intracellular generation of superoxide anion, hydrogen peroxide and hydroxyl radical. ROS induced by chronic insulin treatment inhibited insulin signalling and glucose uptake, induced endoplasmic reticulum (ER) stress and JNK activation. Furthermore, these effects were reversed by antioxidants N-acetylcysteine, superoxide dismutase or catalase. These results suggested that ROS, ER stress and JNK pathway are involved in insulin resistance induced by chronic insulin treatment. Therefore, oxidative stress could be a potential interventional target for hyperinsulinemia-induced insulin resistance and related diseases.
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PMID:Chronic insulin treatment causes insulin resistance in 3T3-L1 adipocytes through oxidative stress. 1856 16

Adipocytokines may be the molecular link between obesity and vascular disease. However, the effects of these factors on coronary vascular function have not been discerned. Accordingly, the goal of this investigation was to delineate the mechanisms by which endogenous adipose-derived factors affect coronary vascular endothelial function. Both isolated canine coronary arteries and coronary blood flow in anesthetized dogs were studied with and without exposure to adipose tissue. Infusion of adipose-conditioned buffer directly into the coronary circulation did not change baseline hemodynamics; however, endothelial-dependent vasodilation to bradykinin was impaired both in vitro and in vivo. Coronary vasodilation to sodium nitroprusside was unaltered by adipose tissue. Oxygen radical formation did not cause the impairment because quantified dihydroethidium staining was decreased by adipose tissue and neither a superoxide dismutase mimetic nor catalase improved endothelial function. Inhibition of nitric oxide (NO) synthase with L-NAME diminished bradykinin-mediated relaxations and eliminated the subsequent vascular effects of adipose tissue. In vitro measurement of NO demonstrated that adipose tissue exposure quickly lowered baseline NO and abolished bradykinin-induced NO production. The results indicate that adipose tissue releases factor(s) that selectively impair endothelial-dependent dilation via inhibition of NO synthase-mediated NO production.
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PMID:Endogenous adipose-derived factors diminish coronary endothelial function via inhibition of nitric oxide synthase. 1857 44

OBJECTIVE- Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IkappaB/NFkappaB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS- TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IkappaB/NFkappaB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS- Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB. CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.
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PMID:Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. 1933 85

Levels of antioxidants, activities of free radical scavenging enzymes and extent of lipid peroxidation were determined in the blood of 37 elderly diabetic men and 30 control elderly men, 16 without cardiovascular disease (CVD) and 14 with CVD. The mean +/-S.D. of the ages of the diabetic men was 66+/-5 and those of the control men was 69+/-5, while serum glucose levels of diabetic men were 213+/-81 mg/dl and that of control subjects were 95+/-14 mg/dl. Among the diabetic men, 13 men were obese with body mass index>30, 26 men had poor control of diabetes (glycohemoglobin>7%) and 25 men had retinopathy. The diets of the control and diabetic men were evaluated. Blood samples were collected and analyzed for major endogenous antioxidant defense parameters and lipid peroxidation. The results show that diabetic men had significantly lower blood reduced glutathione levels (p<0.001) and erythrocyte (RBC) CuZn-superoxide dismutase activity (p<0.001) when compared to control groups with or without CVD. There was no significant differences in plasma vitamin E levels and the activities of catalase and glutathione peroxidase in RBC among the three groups. The extent of lipid peroxidation was highest in diabetic patients, intermediate in controls with CVD, and lowest in controls without CVD. The results suggest that a decline of endogenous antioxidant defense capability contributes to oxidative stress in the diabetic elderly patients. Dietary survey showed that there were no differences in the nutrient intakes of diabetic and control groups. It appears that individual dietary advice is needed for a large portion of diabetic patients in view of their poor glycemic control, hypertriglyceridemia and obesity.
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PMID:Blood antioxidant defense system and dietary survey of elderly diabetic men. 1865 5

The postprandial state seems to have a direct influence on oxidative status and insulin resistance. We determined the effect of an increase in plasma triglycerides after a high-fat meal on oxidative stress in severely obese patients with differing degrees of insulin resistance. The study was undertaken in 60 severely obese persons who received a 60-g fat overload with a commercial preparation. Measurements were made of insulin resistance, the plasma activity of various antioxidant enzymes, the total antioxidant capacity (TAC) and the plasma concentration of thiobarbituric acid reactive substances (TBARS). The patients with greater insulin resistance had a lower plasma superoxide dismutase (SOD) activity (P < 0.05) and a greater glutathione peroxidase (GSH-Px) activity (P < 0.05). The high-fat meal caused a significant reduction in SOD activity and an increase in the plasma concentration of TBARS in all the patients. Only the patients with lower insulin resistance experienced a significant increase in plasma catalase activity (2.22 +/- 1.02 vs. 2.93 +/- 1.22 nmol/min/ml, P < 0.01), remaining stable in the patients with greater insulin resistance. These latter patients had a reduction in plasma TAC (6.92 +/- 1.93 vs. 6.29 +/- 1.80 mmol/l, P < 0.01). In conclusion, our results show a close association between the degree of insulin resistance and markers of oxidative stress, both before and after a high-fat meal. The postprandial state causes an important increase in oxidative stress, especially in severely obese persons with greater insulin resistance. However, we are unable to determine from this study whether there is first an increase in oxidative stress or in insulin resistance.
Obesity (Silver Spring) 2009 Feb
PMID:Oxidative stress in severely obese persons is greater in those with insulin resistance. 1902 78

Cardiovascular disease (CVD) remains the leading cause of morbidity and premature mortality in both women and men in most industrialized countries, and has for some time also established a prominent role in developing nations. In fact, obesity, diabetes mellitus and hypertension are now commonplace even in children and youths. Regular exercise is rapidly gaining widespread advocacy as a preventative measure in schools, medical circles and in the popular media. There is overwhelming evidence garnered from a number of sources, including epidemiological, prospective cohort and intervention studies, suggesting that CVD is largely a disease associated with physical inactivity. A rapidly advancing body of human and animal data confirms an important beneficial role for exercise in the prevention and treatment of CVD. In Part 1 of this review we discuss the impact of exercise on CVD, and we highlight the effects of exercise on (i) endothelial function by regulation of endothelial genes mediating oxidative metabolism, inflammation, apoptosis, cellular growth and proliferation, increased superoxide dismutase (SOD)-1, down-regulation of p67phox, changes in intracellular calcium level, increased vascular endothelial nitric oxide synthase (eNOS), expression and eNOS Ser-1177 phosphorylation; (ii) vascular smooth muscle function by either an increased affinity of the Ca2+ extrusion mechanism or an augmented Ca2+ buffering system by the superficial sarcoplasmic reticulum to increase Ca2+ sequestration, increase in K+ channel activity and/or expression, and increase in L-type Ca2+ current density; (iii) antioxidant systems by elevation of Mn-SOD, Cu/Zn-SOD and catalase, increases in glutathione peroxidase activity and activation of vascular nicotinamide adenine dinucleotide phosphate [(NAD(P)H] oxidase and p22phox expression; (iv) heat shock protein (HSP) expression by stimulating HSP70 expression in myocardium, skeletal muscle and even in human leucocytes, probably through heat shock transcription factor 1 activity; (v) inflammation by reducing serum inflammatory cytokines such as high-sensitivity C-reactive protein (hCRP), interleukin (IL)-6, IL-18 and tumour necrosis factor-alpha and by regulating Toll-like receptor 4 pathway. Exercise also alters vascular remodelling, which involves two forms of vessel growth including angiogenesis and arteriogenesis. Angiogenesis refers to the formation of new capillary networks. Arteriogenesis refers to the growth of pre-existent collateral arterioles leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries. Another aim of this review is to focus on exercise-related cardiovascular protection against CVD and associated risk factors such as aging, coronary heart disease, hypertension, heart failure, diabetes mellitus and peripheral arterial diseases mediated by vascular remodelling. Lastly, this review examines the benefits of exercise in mitigating pre-eclampsia during pregnancy by mechanisms that include improved blood flow, reduced blood pressure, enhanced placental growth and vascularity, increased activity of antioxidant enzymes, reduced oxidative stress and restored vascular endothelial dysfunction.
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PMID:Exercise, vascular wall and cardiovascular diseases: an update (Part 1). 1902 18

Muscle resistance to insulin plays a key role in the metabolic dysregulation associated to obesity. A pro-inflammatory and pro-oxidant status has been proposed to be the link between dietary obesity and insulin resistance. Given the gender differences previously found in mitochondrial function and oxidative stress, the aim of the present study was to investigate whether this gender dimorphism leads to differences in the development of high-fat-diet-induced insulin resistance in rat skeletal muscle. Male and female rats of 15 months of age were fed with a high-fat-diet (32% fat) for 14 weeks. Control male rats showed a more marked insulin resistance status compared to females, as indicated by the glucose tolerance curve profile and the serum insulin, resistin and adiponectin levels. High-fat-diet feeding induced an excess of body weight of 16.2% in males and 38.4% in females, an increase in both muscle mitochondrial hydrogen peroxide production and in oxidative damage, together with a decrease in the Mn-superoxide dismutase activity in both genders. However, high-fat-diet fed female rats showed a less marked insulin resistance profile than males, higher mitochondrial oxygen consumption and cytochrome c oxidase activity, and a better capacity to counteract the oxidative-stress-dependent insulin resistance through an overexpression of both muscle UCP3 and GLUT4 proteins. These results point to a gender dimorphism in the insulin resistance status and in the response of skeletal muscle to high-fat-diet feeding which could be related to a more detrimental effect of age in male rats.
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PMID:Gender dimorphism in high-fat-diet-induced insulin resistance in skeletal muscle of aged rats. 1908 36


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