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)

An increased prevalence and incidence of cardiovascular disease is the most important clinical consequence of abdominal obesity. Although defects in glucose handling in skeletal muscle have been extensively investigated, they have failed to clarify why insulin resistance is linked to vascular disease. Non-classic actions of insulin such as those on haemodynamics, nerve function and haemostasis and on lipoprotein metabolism would appear of greater interest in this respect. It is now clear that obese individuals exhibit resistance to some of the non-classic effects of insulin. These include resistance to insulin action on large vessel compliance, nitric oxide-dependent stimulation of vasodilation in resistance vessels, activation of the sympathetic nervous system by insulin but not other stimuli, platelet anti-aggregation and suppression of hepatic very low density lipoprotein production. The exact cause(s) of resistance to these non-classic insulin actions are unclear but their understanding would seem important to understand the links between obesity and cardiovascular disease.
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PMID:Vascular actions of insulin in obesity. 1099 3

Uncoupling protein-2 (UCP-2) is a mitochondrial protein expressed in adipocytes and has recently been involved in the control of energy dissipation. Because obesity is characterized by an imbalance between energy intake and expenditure and by an enhanced adipocyte-derived secretion of tumor necrosis factor-alpha (TNF-alpha), we asked whether TNF-alpha could directly influence UCP-2 expression in adipocytes. Experiments performed in differentiated 3T3F442A preadipocytes showed that TNF-alpha (10 ng/ml) induced a reduction of UCP-2 trancripts, assessed by Northern blot analysis. A significant decrease in UCP-2 expression (40%) was observed after 12 and 24 h of TNF-alpha stimulation of the cells. The characterization of the mechanisms responsible for the TNF-alpha effect on UCP-2 expression demonstrates an involvement of the TNF-alpha-induced inducible (i) nitric oxide synthase (NOS) expression. Cell treatment with the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mmol/l) significantly diminished the TNF-alpha-mediated sustained downregulation of UCP-2 expression, whereas cell treatment with a nitric oxide (NO) donor (10(-3) mol/l S-nitroso-L-glutathione) mimicked the TNF-alpha effect on UCP-2 expression. Moreover, Western blot analysis clearly showed that TNF-alpha alone induces the expression of iNOS after 12-24 h treatment of differentiated 3T3F442A cells. These experiments demonstrate that TNF-alpha directly downregulates UCP-2 expression via NO-dependent pathways that involve the induction of iNOS expression.
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PMID:Nitric oxide-dependent downregulation of adipocyte UCP-2 expression by tumor necrosis factor-alpha. 1100 90

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g., arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and short life span). We have previously shown that mice heterozygous for a defect in the klotho gene upon parabiosis with wild-type mice show improved endothelial function, suggesting that the klotho gene product protects against endothelial dysfunction. In the present study, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat which demonstrates multiple atherogenic risk factors (e.g., hypertension, obesity, severe hyperglycemia, and hypertriglyceridemia) and is thus considered an experimental animal model of atherosclerotic disease, we show that adenovirus-mediated klotho gene delivery can (1) ameliorate vascular endothelial dysfunction, (2) increase nitric oxide production, (3) reduce elevated blood pressure, and (4) prevent medial hypertrophy and perivascular fibrosis. Based on these findings, klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function (e.g., hypertension and vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease.
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PMID:In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. 1102 45

S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P <.05). Treatment with S15261 or S15511 decreased plasma insulin levels in fed rats and prevented the postprandial peak in insulin levels in a meal tolerance test. Y415 had no effect on insulin levels. Troglitazone halved the insulin response to the test meal, but metformin gave no improvement. S15261 decreased the expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase and stimulated the expression of acetyl-CoA carboxylase and acyl-CoA synthase. S15261 also reduced the expression of carnitine palmitoyltransferase I and hydroxymethyl-glutaryl-CoA synthase. S15261, but not troglitazone, reduced the exaggerated contractile response of mesenteric resistance vessels to norepinephrine, and increased the maximal nitric oxide-mediated relaxation. S15261, through S15511, increased insulin sensitivity, decreased insulin levels, and reduced the vasculopathy of the JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.
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PMID:Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat. 1104 15

L-Arginine (Arg) is the substrate for the synthesis of nitric oxide (NO), the endothelium-derived relaxing factor essential for regulating vascular tone and hemodynamics. NO stimulates angiogenesis, but inhibits endothelin-1 release, leukocyte adhesion, platelet aggregation, superoxide generation, the expression of vascular cell adhesion molecules and monocyte chemotactic peptides, and smooth muscle cell proliferation. Arg exerts its vascular actions also through NO-independent effects, including membrane depolarization, syntheses of creatine, proline and polyamines, secretion of insulin, growth hormone, glucagon and prolactin, plasmin generation and fibrinogenolysis, superoxide scavenging and inhibition of leukocyte adhesion to nonendothelial matrix. Compelling evidence shows that enteral or parenteral administration of Arg reverses endothelial dysfunction associated with major cardiovascular risk factors (hypercholesterolemia, smoking, hypertension, diabetes, obesity/insulin resistance and aging) and ameliorates many common cardiovascular disorders (coronary and peripheral arterial disease, ischemia/reperfusion injury, and heart failure). Dietary Arg supplementation may represent a potentially novel nutritional strategy for preventing and treating cardiovascular disease.
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PMID:Arginine nutrition and cardiovascular function. 1105 97

Nitric oxide (NO) produced by the endothelium of cerebral arterioles is an important mediator of endothelium-dependent vasodilation (EDV), and also helps to prevent thrombosis and vascular remodeling. A number of risk factors for ischemic stroke are associated with impaired EDV, and this defect is usually at least partially attributable to a decrease in the production and/or stability of NO. These risk factors include hypertension, high-sodium diets, homocysteine, diabetes, visceral obesity, and aging. Conversely, many measures which may provide protection from ischemic stroke - such as ample dietary intakes of potassium, arginine, fish oil, and selenium - can have a favorable impact on EDV. Protection afforded by exercise training, estrogen replacement, statin drugs, green tea polyphenols, and cruciferous vegetables may reflect increased expression of the endothelial NO synthase. IGF-I activity stimulates endothelial NO production, and conceivably is a mediator of the protection associated with higher-protein diets in Japanese epidemiology and in hypertensive rats. These considerations prompt the conclusion that modulation of NO availability is a crucial determinant of risk for ischemic stroke. Multifactorial strategies for promoting effective cerebrovascular NO activity, complemented by measures that stabilize platelets and moderate blood viscosity, should minimize risk for ischemic stroke and help maintain vigorous cerebral perfusion into ripe old age. The possibility that such measures will also diminish risk for Alzheimer's disease, and slow the normal age-related decline in mental acuity, merits consideration. A limited amount of ecologic epidemiology suggests that both stroke and senile dementia may be extremely rare in cultures still consuming traditional unsalted whole-food diets. Other lines of evidence suggest that promotion of endothelial NO activity may decrease risk for age-related macular degeneration.
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PMID:Up-regulation of endothelial nitric oxide activity as a central strategy for prevention of ischemic stroke - just say NO to stroke! 1105 18

Obesity is a major health care problem and is associated with significant cardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipose tissue, is important in modulating obesity by signaling satiety and increasing metabolism. Moreover, leptin receptors are expressed on vascular endothelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregulatory mechanisms in the leptin-deficient obese (ob/ob) mouse model and determined the influence of leptin replacement on endothelial-dependent vasorelaxant responses. The direct effect of leptin on EC nitric oxide (NO) production was also tested by using 4, 5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor responses to phenylephrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibition. Vasorelaxant responses to ACh were markedly attenuated in mesenteric microvessels from ob/ob mice. Leptin replacement resulted in significant weight loss and reversal of the impaired endothelial-dependent vasorelaxant responses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate marked abnormalities in vasoregulation, including impaired endothelial-dependent vasodilation, which is reversed by leptin replacement. These findings may be partially explained by the direct effect of leptin on endothelial NO production. These vascular abnormalities are similar to those observed in obese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesity.
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PMID:Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice. 1109 May 93

It is proposed that an important function of leptin is to confine the storage of triglycerides (TG) to the adipocytes, while limiting TG storage in nonadipocytes. Excess TG deposition in nonadipocytes leads to impairment of functions, increased ceramide formation, which triggers nitric oxide-mediated lipotoxicity and lipoapoptosis. The fact that TG content in nonadipocytes normally remains within a very narrow range irrespective of excess caloric intake, while TG content of adipocytes rises, is consistent with a system of fatty acid (FA) homeostasis in nonadipose tissues. When leptin is deficient or leptin receptors are dysfunctional, TG content in nonadipose tissues such as pancreatic islets, heart and skeletal muscle, can increase 10-50-fold, suggesting that leptin controls the putative homeostatic system for intracellular TG. The fact that function and viability of nonadipocytes is compromised when their TG content rises above normal implies that normal homeostasis of their intracellular FA is critical for prevention of complications of obesity. FA overload of skeletal muscle, myocardium and pancreatic islets cause, respectively, insulin resistance, lipotoxic heart disease and adipogenic type 2 diabetes. All can be completely prevented by treatment with antisteatotic agents such as troglitazone. In diet-induced obesity, leptin signaling is normal initially and lipotoxic changes are at first prevented; later, however, post-receptor leptin resistance appears, leading to dysfunction and lipoapoptosis in nonadipose tissues, the familiar complications of obesity.
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PMID:Lipotoxic diseases of nonadipose tissues in obesity. 1112 36

In an open-label self-controlled study of 1,350 patients with stable angina pectoris (SAP), we previously demonstrated that 50 mg of isosorbide mononitrate (ISMN) slow release formulation once daily not only provided a better antianginal effect but also a better quality of life (QOL) than did the daily administration of multiple small doses of the compound. It is unknown whether certain patient characteristics contribute to this benefit. The objective of this article was to determine what independent factors contribute to this benefit. Multiple linear regression analysis was performed on the data from these 1,350 patients. Quality of life was assessed by the Marquis QOL-questionnaire for patients with angina and included the domains of immobility, pain, and psychological distress. For the purpose of this study, overall QOL was calculated as the pooled sums of the domain scores and expressed as mean scores on an ordinal scale of 10. Age did not influence the beneficial effect of nitrate therapy on QOL. Neither did gender, rhythmic disturbances, peripheral artery disease, or the concomitant use of calcium channel blockers or beta blockers. New York Heart Association (NYHA) angina classification was an independent variable: patients with a NYHA class I or II benefited less than did patients with NYHA III or IV (p = 0.02). Obese patients as well as hypertensive patients benefited less (p = 0.04 and 0.02), and smokers tended to benefit less also (p = 0.08). In contrast, hypercholesterolemia and diabetes mellitus improved the beneficial effect of nitrates on QOL (p = 0.03 and 0.05). The authors conclude that patients with coronary artery disease (CAD) and concomitant diabetes mellitus or hypercholesterolemia, a category particularly prone to early endothelial dysfunction and thus dysfunctional endogenous nitric oxide (NO) production, may benefit more from NO-donor therapy than patients without such concomitant conditions.
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PMID:Factors influencing efficacy of nitrate therapy for stable angina pectoris: a multiple linear regression analysis. 1113 92

Obesity is associated with profound alterations of the cardiovascular system including an increase in systemic blood pressure. Several vasoactive factors, including non-esterified fatty acids, angiotensin II, prostaglandins, and nitric oxide are known to be produced by adipose tissue, and are therefore of particular interest regarding their potential role for the regulation of vascular tone and structure. In addition, central nervous system actions of the adipose tissue-derived hormone leptin may contribute to increased sympathetic nervous system activity that is typically found in obesity. Enhanced leptin-driven renal sympathetic out-flow, in combination with low atrial natriuretic peptide plasma levels possibly due to over-expression of the natriuretic peptide clearance receptor in adipocytes, may enhance sodium retention and volume expansion, both key features in the pathophysiology of obesity-associated hypertension. In this review, we discuss these and other possible contributions of adipose tissue to the regulation of cardiovascular-renal function and speculate on the role of adipose tissue for the development of obesity-associated hypertension.
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PMID:Role of adipose tissue for cardiovascular-renal regulation in health and disease. 1124 14


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