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

The level of proteinuria is one of the most important risk factors for progressive renal function loss in renal diseases. Any therapeutic measure that reduces proteinuria will slow or halt the progression of proteinuric nephropathies. Blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors or AT1-receptor antagonists (ARA) is currently the most powerful available antiproteinuric treatment. Recent investigations point out that blockade of RAAS at other levels (e.g., aldosterone or renin antagonists) could also induce a significant decrease in proteinuria. Because angiotensin II is also generated from angiotensin I by enzymes other than ACE, ARA would provide a more effective blockade of angiotensin II; however, ACE inhibition increases plasma levels of substances such as bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline, which have strong antifibrotic properties. These differential effects of ACE inhibitors and ARA are the rationale for combined administration of both agents, which in clinical studies has demonstrated a significantly higher antiproteinuric and renoprotective effect than by either drug alone. Salt and protein restriction, as well as cautious use of diuretics, can also increase the antiproteinuric effect of RAAS blockade. Treatment with statins or other lipid-lowering agents leads to reduction in proteinuria levels, as some meta-analyses have demonstrated. Smoking is associated with an increased risk for the appearance of proteinuria, so cessation of smoking should be mandatory in proteinuric renal diseases. Recent studies have highlighted an epidemic increase of obesity-related proteinuric glomerulopathies; weight loss is effective not only in this condition, but also in overweight patients with proteinuric nephropathies of other etiologies.
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PMID:Therapeutic measures in proteinuric nephropathy. 1633 67

Adiponectin is a fat cell-secreted hormone with antidiabetic and anti-inflammatory activities. The reduced adiponectin levels are associated with obesity-related metabolic syndrome. Replenishment of this hormone into animal models can improve insulin sensitivity, decrease blood glucose and lipid levels, and prevent the development of atherosclerosis and fatty liver injury. Despite these findings, the underlying molecular mechanisms remain largely unknown. Here, we have used affinity chromatography to purify the protein complexes that are associated with adiponectin in human serum. The nature of these adiponectin-binding proteins was analyzed by MS/MS. Eight proteins from the adiponectin-containing protein mixtures have been identified. Many of them, including thrombospondin-1 (TSP-1), histidine-rich glycoprotein, kininogen 1, and alpha 2 macroglobulin (alpha2M), are well-known glycoproteins involved in the regulation of inflammation, angiogenesis, and tissue remodeling. Coimmunoprecipitation and radioligand competitive-binding assays confirmed the direct interactions between adiponectin and alpha2M, or TSP-1. Moreover, these specific bindings were also detected in the serum samples derived from both healthy human subjects and patients with type 2 diabetes. In summary, our study demonstrated that, in the circulation, adiponectin forms protein complexes with other serum proteins. These proteins might serve as the physiological-binding partners of adiponectin and regulate its bioavailability and biological activities.
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PMID:Proteomic characterization of human serum proteins associated with the fat-derived hormone adiponectin. 1676 90

Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.
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PMID:Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation. 1690 96

Kinins are vasoactive and pro-inflammatory peptides generated by the cleavage of the kininogen by kallikreins. Two kinin receptors have been described and denominated B1 and B2. Obesity frequently accompanies other pathologies, such as diabetes and hypertention. The clustering of these pathologies is usually known as "metabolic syndrome". Mice lacking leptin gene (ob/ob) are severely obese and hyperphagic. Using quantitative RT-PCR analysis of B1 and B2 mRNAs expression, we described for the first time a correlation between the kallikrein-kinin system (KKS) and severe obesity in mice. The ob/ob mice presented lower expression of B2 mRNA in the white adipose tissue (WAT) and hypothalamus, both primary sites for neuroendocrine regulation of the energetic metabolism. B1 mRNA, however, is overexpressed in these tissues of ob/ob mice. An upregulation of the B1 mRNA has also been seen in liver, abdominal aorta and stomach fundus. However, different from the lean mice, the expression of the B1 mRNA in brown adipose tissue (BAT) and heart is completely abolished. Our data show that kinin receptors are differently modulated in distinct tissues in obesity. These findings suggest a connection between the KKS and obesity, and suggest that kinin receptors could be involved in the ethiopathogenesis of the metabolic syndrome.
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PMID:Leptin deficiency leads to the regulation of kinin receptors expression in mice. 1718 56

Cardiovascular diseases (CDs) are among the most encountered pathologies in western countries; with obesity reaching pandemic proportions, they are soon to become a worldwide problem. High blood pressure is the main risk factor for CDs, and its tight control is an imperative for the treatment of complications such as renal diseases, heart failure, and atherosclerosis. Blood homeostasis and vascular tone are regulated through at least 3 major closely interrelated pathways in which zinc metallopeptidases modulate the concentration of vasoactive mediators. Those extensively studied vasopeptidases were therefore rapidly targeted with specific inhibitors in order to control the levels of vasoconstrictors [angiotensin II (AII) and endothelin-1 (ET-1)] and vasodilators [bradykinin (BK) and atrial natriuretic peptide (ANP)], thereby controlling blood pressure. The first class of inhibitors to be developed were against angiotensin-converting enzyme (ACE), recently followed by dual inhibitors of ACE/neprylisin (NEP), NEP/endothelin-converting enzyme (ECE), and finally triple ACE/NEP/ECE inhibitors. The dual and triple inhibitors are defined as vasopeptidase inhibitors (VPI). In addition to their ability to effectively lower blood pressure in hypertensive patients, drugs targeting these enzymes also displayed antiinflammatory and antifibrotic activities. The major point emerging from recent studies undertaken to improve the management of CDs is that the combined action of different therapeutic strategies (ie, simultaneous modulation of several neurohumoral mediators) shows better results than conservative therapeutic approaches. In this review, we historically present the advances made in the comprehension of the different mechanisms of blood pressure regulation and some of the drugs that arose from this understanding.
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PMID:Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases. 1787 51

The metabolic syndrome (MetS) often accompanies obesity and contributes to the increased risk of atherothrombotic events with increased body fatness. Indeed, the risks for coronary artery disease and acute vascular events are greater with obesity combined with MetS compared with obesity alone. Endothelial release of tissue-type plasminogen activator (t-PA) is a key defense mechanism against thrombosis and has been shown to be impaired with obesity. The aim of the present study was to determine whether the presence of MetS exacerbates endothelial fibrinolytic dysfunction in obese adults. Net endothelial release of t-PA was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside in 47 sedentary adults: 15 normal weight (age 57 +/- 2 yr; body mass index 22.9 +/- 0.5 kg/m(2)), 14 obese but otherwise healthy (55 +/- 1 yr; 29.4 +/- 0.3 kg/m(2)), and 18 obese with MetS (55 +/- 2 yr; 32.3 +/- 1 kg/m(2)). MetS was established according to National Cholesterol Education Program ATP III criteria. Net release of t-PA antigen to bradykinin was approximately 50% lower (P < 0.01) in the obese (from 2.5 +/- 1.9 to 37.1 +/- 5.3 ng.100 ml tissue(-1).min(-1)) and obese with MetS (from 0.4 +/- 0.8 to 32.5 +/- 3.8 ng.100 ml tissue(-1).min(-1)) compared with normal-weight (from 0.9 +/- 1.0 to 74.3 +/- 8.1 ng.100 ml tissue(-1).min(-1)) subjects. However, there were no significant differences in the capacity of the endothelium to release t-PA in the obese and obese with MetS adults. These results indicate that the presence of the MetS does not worsen the obesity-related endothelial fibrinolytic dysfunction.
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PMID:Metabolic syndrome and endothelial fibrinolytic capacity in obese adults. 1795 3

BBZDR/Wor rat is a new model of type II diabetes with spontaneous obesity and clinical characteristics close to human diabetes. In this study the time-course of cerebroarterial dysfunction was characterized. Posterior cerebral arteries from BBZDR/Wor rats and their age-matched lean controls were pressurized to 70 mm Hg in an arteriograph. Effects of intraluminal pressure and different pharmacological agents on myogenic tone were evaluated. Pressure-myogenic tone curves in diabetic arteries were similar to that in non-diabetic arteries at pre-diabetic age, showed leftward shift at 4 weeks and were significantly different with higher myogenic tone at 5 and 8 months of diabetes. Age-dependent decrease in myogenic tone was observed in non-diabetic arteries. Dilation to histamine was similar to that in non-diabetic arteries at pre-diabetic and at 4 weeks but significantly reduced at 5 and 8 months of diabetes. Bradykinin-mediated dilation was significantly reduced in early and chronic diabetes, whereas (+/-)-S-nitroso-N-acetylpenicillamine (SNAP)-mediated dilation was decreased modestly at 8 months of diabetes. Sensitivity and constriction to 5-hydroxytryptamine were increased in early and chronic diabetes. Responses to bradykinin and 5-hydroxytryptamine were decreased and increased, respectively. Myogenic tone was significantly less sensitive to (lower pIC(50)) U-73122 than normal arteries at 4 weeks and 8 months of diabetes suggesting an increased activation of phospholipase C (PLC). This study shows that pressure-mediated autoregulation of cerebral arteries in type II diabetes operates at higher resistance. Endothelium-dependent dilation was decreased with chronic diabetes with increased sensitivity to constrictor agonist. Endothelium-independent dilation was modestly affected. Arterial hyper-reactivity to pressure and constrictor agonist were likely due to increased PLC activation.
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PMID:Myogenic tone and reactivity of cerebral arteries in type II diabetic BBZDR/Wor rat. 1803 20

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.
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PMID:Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists. 1828 79

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

Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.
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PMID:Leptin regulates ACE activity in mice. 2069 85


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