Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Upper body obesity is associated with insulin resistance, hypertension, and endothelial dysfunction. We examined forearm vascular function in response to vasodilator (endothelium-dependent and endothelium-independent) and vasoconstrictor stimuli in 8 normotensive, upper body/viscerally obese men with a positive family history of hypertension and 8 age-matched nonobese men. We also measured body composition and insulin regulation of free fatty acid (FFA) and glucose metabolism. Forearm blood flow was measured before and during brachial artery infusions of acetylcholine (Ach), sodium nitroprusside (NTP), and angiotensin II (+/-nitric oxide synthase [NO]) synthase blockade with N(G)-monomethyl L-arginine [L-NMMA]). On a separate day, baseline and insulin-regulated glucose ([3-3H]glucose) and FFA ([9,10-3H]palmitate) turnover were measured. The vasoconstrictor response to angiotensin II was greater (P<0.05) in obese men than in nonobese men, whereas endothelium-dependent vasodilation was similar. The slope of the angiotensin II dose-response curve correlated significantly with the basal plasma palmitate concentration. Basal and insulin-mediated glucose disposal was significantly reduced and FFA turnover significantly increased in viscerally obese men. No differences in endothelium-independent vasodilation or relationships between vascular responsivity and palmitate and glucose kinetics or body composition were found. Angiotensin II-stimulated forearm vasoconstriction is increased in viscerally obese normotensive men.
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PMID:Vascular response to angiotensin II in upper body obesity. 1533 33

Studies on the associations between the nitric oxide synthase gene (NOS3) Glu298Asp polymorphism and hypertension status or blood pressure (BP) levels have had inconsistent results. Potential moderating influences of ethnicity, sex, and obesity on the effects of the NOS3 polymorphism have not been examined. We evaluated the influence of these factors on associations between the NOS3 polymorphism, nitric oxide metabolites (NOx), and hemodynamics at rest and during stress. Subjects were 235 African American (AA) and 262 European American (EA) young adults (18.5+/-2.6 years). Hemodynamic measurements and blood samples for NOx assays were taken before and after a competitive video game challenge. Glu298Asp polymorphism was detected by polymerase chain reaction-restriction enzyme digestion assay. A regression model was built using genotypes, ethnicity, sex, and obesity (body mass index >85th percentile) and their interactions controlling for age; 20.1% of AAs and 49.8% of EAs were carriers of the Asp allele. AAs, regardless of obesity status, exhibited high diastolic blood pressure (DBP) reactivity unless they were nonobese and noncarriers of the Asp allele. EAs exhibited lower DBP reactivity unless they were obese Asp allele carriers. AA nonobese carriers exhibited the greatest total peripheral resistance reactivity. Obese Asp allele carriers exhibited the greatest increases in cardiac output and the greatest decrease in NOx to the stressor. Results indicate the importance of examining impact of BP control-related genetic polymorphisms within the context of moderating factors such as adiposity and ethnicity.
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PMID:Effects of NOS3 Glu298Asp polymorphism on hemodynamic reactivity to stress: influences of ethnicity and obesity. 1550 16

Obesity and insulin resistance are reaching epidemic proportions worldwide. Over the past decade, nitric oxide (NO) has emerged as a key player in the regulation of the metabolic and cardiovascular homeostasis. Here we will review recent data obtained in mice with disruption of the genes encoding for each of the three nitric oxide synthase isoforms. These data demonstrate that both defective and augmented NO synthesis have detrimental effects on the regulation of the metabolic and cardiovascular system. These observations provide the rationale for the use of NO-donors and/or inhibitors of NO overproduction in the treatment of insulin resistance.
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PMID:[NO, a major regulator of metabolic and cardiovascular homeostasis]. 1557 10

The insulin resistance syndrome, otherwise known as the metabolic syndrome, describes a cluster of cardiovascular and metabolic abnormalities, which are strongly associated with overweight and obesity. The importance of the syndrome is due to its increased rates of cardiovascular morbidity and mortality. Insulin resistance is also characterized by elevated free fatty acid (FFA) levels. In otherwise healthy human subjects, elevation of FFA impairs endothelial function. This appears to be largely the result of blunting of nitric oxide-dependent tone, most likely at the level of the endothelial isoform of nitric oxide synthase (eNOS). Some of the potential mediatory mechanisms include oxidative stress, proinflammatory cytokines, C-reactive protein, or endogenous inhibitors of eNOS. Regardless of the mechanism(s) that mediates the effects of increased FFA on the vasculature, impaired vascular function is likely to account, at least in part, for the increase in cardiovascular mortality in subjects with the insulin resistance syndrome.
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PMID:FFAs: do they play a role in vascular disease in the insulin resistance syndrome? 1566 14

Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.
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PMID:Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome. 1573 83

Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; and 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene is expressed in canine coronary arteries and human coronary endothelium. Furthermore, immunocytochemistry demonstrated that the long-form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (<130 microm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1-3.0 microg/min ic) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated the dilation to graded intracoronary doses of acetylcholine (0.3-30.0 microg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/l-6.25 micromol/l) was significantly attenuated by obese concentrations of leptin (625 pmol/l) but not by physiological concentrations of leptin (250 pmol/l). The major findings of this investigation were as follows: 1) the ObRb is present in coronary arteries and coupled to pharmacological, nitric oxide-dependent vasodilation; and 2) hyperleptinemia produces significant coronary endothelial dysfunction.
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PMID:Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction. 1574 44

Chronic inflammation has been postulated to play an important role in the pathogenesis of insulin resistance. Inducible nitric oxide synthase (iNOS) has been implicated in many human diseases associated with inflammation. iNOS deficiency was shown to prevent high-fat diet-induced insulin resistance in skeletal muscle but not in the liver. A role for iNOS in fasting hyperglycemia and hepatic insulin resistance, however, remains to be investigated in obesity-related diabetes. To address this issue, we examined the effects of a specific inhibitor for iNOS, L-NIL, in obese diabetic (ob/ob) mice. iNOS expression was increased in the liver of ob/ob mice compared with wild-type mice. Treatment with iNOS inhibitor reversed fasting hyperglycemia with concomitant amelioration of hyperinsulinemia and improved insulin sensitivity in ob/ob mice. iNOS inhibitor also increased the protein expression of insulin receptor substrate (IRS)-1 and -2 1.5- and 2-fold, respectively, and enhanced IRS-1- and IRS-2-mediated insulin signaling in the liver of ob/ob mice. Exposure to NO donor and ectopically expressed iNOS decreased the protein expression of IRS-1 and -2 in cultured hepatocytes. These results suggest that iNOS plays a role in fasting hyperglycemia and contributes to hepatic insulin resistance in ob/ob mice.
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PMID:A role for iNOS in fasting hyperglycemia and impaired insulin signaling in the liver of obese diabetic mice. 1585 18

We have developed a primary skeletal muscle cell culture model derived from normal prepubertal children to investigate the effects of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and tumour necrosis factor alpha (TNFalpha) on growth, differentiation and metabolism. Cells of myoblast lineage were characterized morphologically by desmin staining and differentiated successfully into multinucleated myotubes. Differentiation was confirmed biochemically by an increase in creatine kinase (CK) activity and IGFBP-3 secretion over time. IGF-I promoted whilst TNFalpha inhibited myoblast proliferation, differentiation and IGFBP-3 secretion. IGF-I partially rescued the cells from the inhibiting effects of TNFalpha. Compared to adult myoblast cultures, children's skeletal muscle cells demonstrated higher basal and day 7 CK activities, increased levels of IGFBP-3 secretion, diminished IGF-I/TNFalpha action and absence of the inhibitory effect of exogenous IGFBP-3 on differentiation. Additional studies demonstrated that TNFalpha increased basal glucose transport via GLUT1, nitric oxide synthase and p38MAPK-dependent mechanisms. These studies provide baseline data to study the interactivity effects of growth factors and cytokines on differentiation and metabolism in muscle in relation to important metabolic disorders such as obesity, type II diabetes or chronic wasting diseases.
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PMID:Isolation and validation of human prepubertal skeletal muscle cells: maturation and metabolic effects of IGF-I, IGFBP-3 and TNFalpha. 1608 85

Metabolic syndrome is a cluster of metabolic abnormalities, including hypertension, hyperlipidemia, hyperinsulinemia, glucose intolerance and obesity. In such lifestyle-related diseases, impairment of nitric oxide (NO) production or bioactivity has been reported to lead to the development of atherogenic vascular diseases. Therefore, in the present study we investigated changes in the NO/cyclic guanosine monophosphate (cGMP) system in aortas of SHR/NDmcr-cp (cp/cp) rats (SHR-cp), a model of the metabolic syndrome. In aortas of SHR-cp, endothelium-dependent relaxations induced by acetylcholine and endothelium-independent relaxations induced by sodium nitroprusside were significantly impaired in comparison with Wistar-Kyoto rats. Furthermore, protein levels of soluble guanylyl cyclase and cGMP levels induced by sodium nitroprusside were significantly decreased. In contrast, protein levels of endothelium NO synthase and cGMP levels induced by acetylcholine were significantly increased, and plasma NO2 plus NO3 levels were also increased. The levels of lipid peroxide in plasma and the contents of 3-nitrotyrosine, a biomarker of peroxynitrite, in aortas were markedly increased. These findings indicate that in the aortas of SHR-cp, NO production from the endothelium is augmented, although the NO-induced relaxation response is impaired. Enhanced NO production may be a compensatory response to a variety of factors, including increases in oxidative stress.
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PMID:Disturbances in nitric oxide/cyclic guanosine monophosphate system in SHR/NDmcr-cp rats, a model of metabolic syndrome. 1618 78

Type 2 diabetes caused by obesity shows autonomic neuropathy. Molecular mechanism involved in enteric neurodegeneration is not clear. Neuronal nitric oxide synthase (nNOS) is one of the important agents involved in gastrointestinal function. Therefore, expression of nNOS in the duodenum LM-MP of type 2 diabetes model mouse was studied. Real time RT-PCR analysis showed reduction in nNOS expression in male diabetic LM-MP compared to male control. In contrast, female diabetic LM-MP had high level of nNOS mRNA compared to female control. Western blot determination of LM-MP showed reduction in nNOS protein in male diabetic LM-MP and high level of nNOS in female diabetic LM-MP compared to their respective controls. Expression of nNOS observed by Western blot was further confirmed by nNOS immunostaining of the mouse duodenum. TUNEL staining of mouse duodenum showed apoptosis in male diabetic enteric neurons. These studies suggest that nNOS expression in LM-MP varies with gender during early stage of type 2 diabetes. In addition, reduced expression of nNOS is likely to contribute to apoptosis seen in the enteric neurons of male type 2 diabetic mice.
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PMID:Altered expression of neuronal nitric oxide synthase in the duodenum longitudinal muscle-myenteric plexus of obesity induced diabetes mouse: implications on enteric neurodegeneration. 1625 69


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