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

A total of 64 male patients with varying forms of coronary heart disease (CHD), aged 43 to 65 years, and free of diabetes mellitus, obesity and arterial hypertension symptoms, were studied in conditions of emotional stress simulated, using the method of mental calculations with shifts of attention under time shortage. Pre- and post-exercise blood levels of cyclic nucleotides (cAMP and cGMP), the somatotropic hormone and immunoreactive insulin were measured. Stress-induced decrease in platelet cAMP/cGMP ratios, indicative of further increase in the functional activity of platelets, was demonstrated in coronary patients with marked coronary atherosclerosis, as contrasted to normal subjects and patients with milder disease. They also showed a more considerable (sixfold) increase in the somatotropic hormone levels and a tendency to decreased levels of immunoreactive insulin under stress, apparently as a consequence of the prevailing activation of alpha-adrenoreceptor pathways.
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PMID:[Dynamics of cyclase systems and hormonal indices in patients with ischemic heart disease in a state of emotional stress]. 300 51

To investigate the effects of insulin on platelets in obesity and in non-insulin-dependent diabetes mellitus (NIDDM)--classic insulin-resistant states--we determined ADP-induced platelet aggregation and platelet cGMP (guanosine 3',5'-cyclic monophosphate) content in platelet-rich plasma obtained from nine obese subjects and nine age-matched healthy volunteers and from eight NIDDM obese patients and nine age-matched healthy volunteers after a 3-min incubation with human recombinant insulin (0, 240, 480, 960, and 1,920 pmol/l). Platelet aggregation was evaluated using different ADP doses to measure the ADP concentration determined on the basis of a dose-response curve necessary to elicit a maximal aggregation of 50% (ED50). Insulin induced a dose-dependent decrease of platelet aggregation to ADP (P = 0.0001) in healthy subjects. A significant effect was evident starting from an insulin concentration of 240 pmol/l. On the contrary, in insulin-resistant subjects, insulin reduced platelet sensitivity to ADP only at a concentration of 1,920 pmol/l. When ADP ED50 values obtained in platelet-rich plasma incubated with insulin were expressed in percentage of the ADP ED50 values obtained in platelet-rich plasma without insulin, considered as 100%, we observed that ADP ED50 with 1,920 pmol/l insulin was 153.6 +/- 13.2% in the younger healthy subject group (P = 0.004), 150.0 +/- 3.8% in the older healthy subject group (P = 0.0001), 116.1 +/- 6.1% in obese subjects (P = 0.031), and 120.0 +/- 8.6% in NIDDM patients (P = 0.05). In healthy subjects, insulin induced a dose-dependent increase of platelet cGMP (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients. 758 30

We have cloned the coding region of a human gene, whose predicted amino acid sequence shows 88% homology and higher correspondence in functional domains to the rat cGMP inhibited phosphodiesterase gene (PDE3A). In concordance with the expression data of the rat PDE3A gene, a 5.3-kb transcript of the human cGMP-inhibited phosphodiesterase gene is shown in Northern blot analysis to be highly expressed in adipose tissue. In addition, weaker expression is seen in pancreas, skeletal muscle, liver, placenta, and heart. cDNA clones from the homologue mouse gene were isolated and sequenced spanning a highly conserved region coding for a C-terminal located catalytic core region of this enzyme family. Using a genomic cosmid clone of human PDE3A for fluorescence in situ hybridization, the gene was mapped to chromosomal region 11p15 and regionally sublocalized by PCR on a human-hamster somatic hybrid-cell mapping panel to 11p15.1-p2. Based on comparative linkage data in mouse and rat this chromosomal location is suggested to contain genes involved in complex diseases like obesity and diabetes mellitus type II. Therefore, a possible involvement of the human PDE3A gene in these polygenic traits is discussed, taking into account the prominent role of the rat PDE3A gene product in the antilipolytic action of insulin in adipocytes.
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PMID:Molecular cloning and chromosomal assignment of the human homologue of the rat cGMP-inhibited phosphodiesterase 1 (PDE3A)--a gene involved in fat metabolism located at 11p 15.1. 892 98

1. The obese fa/fa Zucker rat is a genetic model of obesity and insulin resistance which develops a number of metabolic and endocrine features of non-insulin-dependent diabetes, including hypertension, proteinuria and glomerular sclerosis. 2. We have investigated the urinary excretion of the metabolites of thromboxane (thromboxane B2) and prostacyclin (6-keto prostaglandin F1 alpha), and of endothelin and cyclic GMP as markers for changes in the balance of renal haemodynamic factors in the obese Zucker rat. 3. Obese fa/fa Zucker rats were hypertensive compared with their lean counterparts (161 +/- 3 and 138 +/- 3 mmHg respectively, P < 0.01); obese animals were also markedly proteinuric (16.7 +/- 6.7 versus 1.1 +/- 0.1 mg/ml) and albuminuric (8.3 +/- 2.9 versus 0.4 +/- 0.25 mg/ml) and excreted less creatinine than lean animals (all P < 0.01). Urinary excretion of endothelin was greater in obese rats (123 +/- 24 versus 62 +/- 10 pg/15 h, P < 0.05) as was the level of pre-proendothelin mRNA, but excretion of cyclic GMP was depressed (12.5 +/- 1.6 versus 27.2 +/- 3.1 nmol/ 15 h, P < 0.01). Histological examination of kidneys from obese animals showed evidence of focal glomerulosclerosis and cortical tubular damage. 4. These results show that increased urinary endothelin is associated with proteinuria and early stage nephropathy in this animal model of non-insulin-dependent diabetes mellitus. This finding, coupled with a decreased excretion of cyclic GMP, suggests that these increased renal vasoconstrictor/vasodilator forces might contribute to the renal functional changes in non-insulin-dependent diabetes mellitus.
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PMID:Elevated renal endothelin-I clearance and mRNA levels associated with albuminuria and nephropathy in non-insulin-dependent diabetes mellitus: studies in obese fa/fa Zucker rats. 949 94

1. The effects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were investigated. 2. Phenylephrine (PE; 0.1 nM-10 microM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium. 3. Acetylcholine (ACh; 0.1 nM-10 microM)-induced endothelium-dependent relaxation of rings was not significantly different in the two genotypes. Both were inhibited to a similar extent by NG-nitro-L-arginine methyl ester (L-NAME; 0.01-1 mM) when administered in vitro. 4. The nitric oxide synthase (NOS) inhibitor (L-NAME; 0.3, 1 or 3 mg ml(-1), p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats. 5. L-NAME resulted in greater inhibition of ACh-induced relaxation in cp/cp rings compared with +/? rings. 6. L-NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats. 7. The NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM-10 microM)-induced relaxation of rings from +/? rats, an effect enhanced by the treatment with L-NAME in vivo. 8. Oral administration of L-NAME did not enhance the vasorelaxant effect of SNAP on rings of aorta from cp/cp animals. 9. Platelet aggregation and NOS activity were similar in both genotypes and were not modified by oral administration of L-NAME. 10. These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exemplified by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.
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PMID:Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin-resistant, obese JCR:LA-cp rats. 964 54

The association between obesity and hypertension is well known but the pathophysiology of weight-related changes on blood pressure is still a matter of debate. Although obesity-related hypertension is considered to be sodium-sensitive, little attention has been given to a possible pathophysiological role of Atrial Natriuretic Peptides (ANP) and their receptors (NPr) system. Since the early phase of weight loss induced by very-low-calorie diet or fasting is followed by a significant increase in diuresis and natriuresis together with an increase in circulating ANP, we focused our attention on the possible role of adipose tissue in mediating these changes. We first demonstrated that human and rat adipose tissue contain high levels of mRNA specific for both type A (NPr-A), which is biologically active, and type C (NPr-C) which is biologically inactive, receptors. We then demonstrated in the rat that fasting exerts a tissue-specific and gene-specific suppression of NPr-C gene expression in adipose tissue that appears to be accompanied by an increased biological activity of ANP. These experimental observations were confirmed in man studying gene expression of NPr-A and NPr-C in adipose tissue obtained through subcutaneous peri-umbilical needle aspiration in obese and non-obese hypertensive patients. We found that NPr-A: NPr-C mRNA ratio was significantly lower in obese hypertensive patients as compared with non-obese hypertensives. These findings suggest that overxpression of the clearance receptor in the obese may trap more molecules of circulating ANP so reducing their biological activity at renal level. More recent results were obtained in obese hypertensive patients in whom the intravenous bolus injection of ANP (0.6 mg/kg body weight) was performed before and after four days of very-low-calorie diet which induced a weight loss accompanied by a significant reduction of BP and an increase in the urinary excretion of cGMP. The infusion of ANP after low-calorie diet was followed by an increase of ANP levels similar to that observed before diet, but plasma cGMP, diuresis and natriuresis significantly increased only after caloric restriction and the effects of ANP infusion on BP were more pronounced. Taken together our studies suggest that the abundance of NPr-C in adipose tissue may play a significant role in explaining at least part of the sodium retention characteristic of obesity associated hypertension.
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PMID:The natriuretic peptide system in obesity-related hypertension: new pathophysiological aspects. 1004 95

Adipose tissue lipolysis, i.e., the catabolic process leading to the breakdown of triglycerides into fatty acids and glycerol, is often considered as a simple and well-understood metabolic pathway. However, progress on the hormonal regulation and molecular mechanism of fat-cell lipolysis is opening new avenues and points to a number of unanswered questions. Recent studies on the lipolytic beta- and antilipolytic alpha2-adrenergic control of lipolysis has allowed a better understanding of the relative contribution of the two types of receptors and provide strong evidence for the in vivo implication of alpha2-adrenoceptors in the physiological control of subcutaneous adipose-tissue lipolysis. A novel lipolytic system has been characterized in human fat cells. Natriuretic peptides stimulate lipolysis through a cGMP-dependent pathway. The molecular details of the lipolytic reaction are not fully understood. Translocation of hormone-sensitive lipase, the rate-limiting enzyme of lipolysis, to the lipid droplet seems to be an important step during lipolytic activation. Reorganization of the lipid droplet coating by perilipins may also facilitate the access of the enzyme. Unexpectedly, hormone-sensitive lipase-deficient mice are not obese and show residual adipose-tissue lipolysis, which suggests the existence of another triglyceride lipase. Whether the expression of this uncharacterized neutral lipase is compensatory for the lack of hormone-sensitive lipase is an important question yet to be resolved. In humans, alterations of hormone-sensitive lipase expression are associated with changes in lipolysis in various physiological and pathological states. Genetic studies show that beta2-adrenoceptor and hormone-sensitive lipase genes may participate in the polygenic background of obesity.
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PMID:Millennium fat-cell lipolysis reveals unsuspected novel tracks. 1124 9

Leptin is a regulator of body weight and affects nitric oxide (NO) production. This study was designed to determine whether the myocardial NO-cGMP signal transduction system was altered in leptin-deficient obese mice. Contractile function, guanylyl cyclase activity, and cGMP-dependent protein phosphorylation were assessed in ventricular myocytes isolated from genetically obese (B6.V-Lepob) and age-matched lean (C57BL/6J) mice. There were no differences in baseline contraction between the lean and obese groups. After stimulation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10-6 and 10-5 M) or a membrane-permeable cGMP analog 8-bromo-cGMP (8-Br-cGMP, 10(-6) and 10(-5) M), cell contractility was depressed. However, 8-Br-cGMP had significantly greater effects in obese mice than in lean controls with percent shortening reduced by 47 vs. 39% and maximal rate of shortening decreased by 46 vs. 36%. The negative effects of SNAP were similar between the two groups. Soluble guanylyl cyclase activity was not attenuated. This suggests that the activity of the cGMP-independent NO pathway may be enhanced in obesity. The phosphorylated protein profile of cGMP-dependent protein kinase showed that four proteins were more intensively phosphorylated in obese mice, which suggests an explanation for the enhanced effect of cGMP. These results indicate that the NO-cGMP signaling pathway was significantly altered in ventricular myocytes from the leptin-deficient obese mouse model.
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PMID:Alterations in nitric oxide-cGMP pathway in ventricular myocytes from obese leptin-deficient mice. 1286 80

Phosphodiesterases (PDEs) are enzymes that modulate cyclic nucleotide signaling and as such are clinical targets for a range of disorders including congestive heart failure, erectile dysfunction, and inflammation. The PDE3 family comprises two highly homologous subtypes expressed in different tissues, and inhibitors of this family have been shown to increase lipolysis in adipocytes. A specific PDE3B (the lipocyte-localized subtype) inhibitor would be a very useful tool to evaluate the effects of PDE3 inhibition on lipolysis and metabolic rate and might become a novel tool for treatment of obesity. We report here the three-dimensional structures of the catalytic domain of human PDE3B in complex with a generic PDE inhibitor and a novel PDE3 selective inhibitor. These structures explain the dual cAMP/cGMP binding capabilities of PDE3, provide the molecular basis for inhibitor specificity, and can supply a valid platform for the design of improved compounds.
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PMID:Crystal structure of human phosphodiesterase 3B: atomic basis for substrate and inhibitor specificity. 1514 93

Hyperleptinemia may be involved in the pathogenesis of obesity-associated hypertension, however, the mechanism of hypertensive effect of leptin has not been elucidated. We investigated the effect of experimental hyperleptinemia on renal function, renal Na(+), K(+)-ATPase and ouabain-sensitive H(+), K(+)-ATPase activities in the rat. Leptin administered for 7 days (0.25 mg/kg twice daily sc) decreased food intake on 6th and 7th day of treatment but had no effect on body weight. Systolic blood pressure was 30.5% higher in leptin-treated animals. Urinary excretion of sodium decreased by 35.0% following leptin treatment. Leptin had no effect on potassium and phosphate excretion as well as on creatinine clearance. The activity of Na(+), K(+)-ATPase in the renal cortex and medulla was higher in leptin-treated rats by 32.4% and 84.2%, respectively. In contrast, leptin had no effect on either cortical or medullary ouabain-sensitive H(+), K(+)-ATPase. In pair-fed group, in which food intake was reduced to the level observed in leptin-treated group, no changes in sodium metabolism and renal Na(+), K(+)-ATPase were observed. Leptin decreased urinary excretion of nitric oxide metabolites by 55.0% and urinary excretion of cGMP by 26.3%. Plasma concentration of atrial natriuretic peptide tended to be higher and urinary excretion of urodilatin was 64.9% higher in leptin-treated animals. These data suggest that hyperleptinemia decreases natriuresis by up-regulating Na(+), K(+)-ATPase and stimulating tubular sodium reabsorption. This effect is mediated, at least in part, by deficiency of nitric oxide (NO). Abnormal renal sodium retention and vasoconstriction associated with NO deficiency may contribute to leptin-induced hypertension and to blood pressure elevation in hypertensive obese individuals.
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PMID:Up-regulation of renal Na+, K+-ATPase: the possible novel mechanism of leptin-induced hypertension. 1515 72


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