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)

Cardiovascular diseases like hypertension, hyperlipidemia, diabetes mellitus and obesity are the important predictors of erectile dysfunction (ED). Endothelial dysfunction is proposed to be the underlying cause of ED, just like coronary artery disease. Sildenafil was originally developed to treat angina pectoris but later on was recognized as novel treatment option for impotence. To date, sildenafil has been the most extensively studied PDE (phosphodiesterase)-5 inhibitor. Currently two more PDE-5 inhibitors, tadalafil and vardenafil, are under study. Newer compounds have certain advantages over sildenafil, including greater selectivity for PDE-5 compared with other isoenzymes, absence of effect of food on absorption, faster onset and longer duration of action. PDE-5 inhibitors are emerging as novel therapeutic tools with a potential to protect or enhance endothelial function in humans and to selectively improve regional blood flow. The FDA has recently approved a reformulation of sildenafil for the treatment of pulmonary arterial hypertension. Raynaud's phenomenon, respiratory disorders with ventilation/ perfusion mismatch, congestive cardiac failure, hypertension and stroke are the other conditions in which PDE-5 inhibitors are being tried. It is hoped that this group of drugs will soon emerge as a novel weapon in the armamentarium against various cardiovascular and pulmonary diseases.
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PMID:Novel phosphodiesterase-5 inhibitors: current indications and future directions. 1817 38

The release of fatty acids and glycerol from lipid droplets (LD) of mammalian adipose cells is tightly regulated by a number of counterregulatory signals and negative feedback mechanisms. In humans unrestrained lipolysis contributes to the pathogenesis of obesity and type II diabetes. In order to identify novel targets for the pharmacological interference with lipolysis, the molecular mechanisms of four antilipolytic agents were compared in isolated rat adipocytes. Incubation of the adipocytes with insulin, palmitate, glucose oxidase (for the generation of H2O2) and the antidiabetic sulfonylurea drug, glimepiride, reduced adenylyl cyclase-dependent, but not dibutyryl-cAMP-induced lipolysis as well as the translocation of hormone-sensitive lipase and the LD-associated protein, perilipin-A, to and from LD, respectively. The antilipolytic activity of palmitate, H2O2 and glimepiride rather than that of insulin was dependent on rolipram-sensitive but cilostamide-insensitive phosphodiesterase (PDE) but was not associated with detectable downregulation of total cytosolic cAMP and insulin signaling via phosphatidylinositol-3 kinase and protein kinase B. LD from adipocytes treated with palmitate, H2O2 and glimepiride were capable of converting cAMP to adenosine in vitro, which was hardly observed with those from basal cells. Conversion of cAMP to adenosine was blocked by rolipram and the 5'-nucleotidase inhibitor, AMPCP. Immunoblotting analysis revealed a limited salt-sensitive association with LD of some of the PDE isoforms currently known to be expressed in rat adipocytes. In contrast, the cAMP-to-adenosine converting activity was stripped off the LD by bacterial phosphatidylinositol-specific phospholipase C. These findings emphasize the importance of the compartmentalization of cAMP signaling for the regulation of lipolysis in adipocytes, in general, and of the involvement of LD-associated proteins for cAMP degradation, in particular.
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PMID:Inhibition of lipolysis by palmitate, H2O2 and the sulfonylurea drug, glimepiride, in rat adipocytes depends on cAMP degradation by lipid droplets. 1818 16

Arterial stiffness is an independent risk factor for premature cardiovascular morbidity and mortality that can be evaluated by noninvasive methods and can be reduced by good clinical management. The present chapter examines the association between arterial stiffness and cardiovascular risk factors including hypertension, metabolic syndrome, diabetes, advanced renal failure, hypercholesterolemia and obesity. The mechanisms responsible for the structural and functional modifications of the arterial wall are also described. We deal with parameters related to arterial compliance, focusing on two of them, pulse wave velocity and the augmentation index, useful in rapid assessment of arterial compliance by the bedside. Data that highlight the role of aortic pulse wave velocity and the augmentation index as independent factors in predicting fatal and nonfatal cardiovascular events in different populations are briefly presented. A number of lifestyle changes and traditional antihypertensive agents that improve arterial compliance are finally discussed. Novel therapies, such as statins, thiazolidindinediones, phosphodiesterase inhibitors and inhibitors or breakers of advanced glycation end product cross-links between colagen and elastin hold substantial promise.
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PMID:Arterial elasticity in cardiovascular disease: focus on hypertension, metabolic syndrome and diabetes. 1823 Sep 56

The K121Q variant of the ectonucleotide pyrophosphatase/ phosphodiesterase 1 (ENPP1) gene is associated with obesity, insulin resistance, and early myocardial infarction. Therefore, we hypothesized that the K121Q polymorphism might also be associated with an increased risk for peripheral arterial disease. Four hundred patients with peripheral arterial disease and 400 controls matched for sex and age (+/- 2 years) were genotyped cross-sectionally for the K121Q single nucleotide polymorphism of the ENPP1 gene. The frequency for the 121Q allele was 0.25 both in patients with peripheral arterial disease and in controls (P = 0.75). Subgroup analysis revealed association of the ENPP1 121QQ genotype with higher glycohemoglobin A1C levels (P = 0.001) and earlier onset of peripheral arterial disease (P = 0.003) in the cohort of nonsmokers. Whereas the K121Q genotype of the ENPP1 gene is not associated with presence of peripheral arterial disease in the whole Linz Peripheral Arterial Disease population, it is associated with type 2 diabetes mellitus and earlier onset of peripheral arterial disease in the subgroup of nonsmoking patients.
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PMID:The K121Q polymorphism of ENPP1 and peripheral arterial disease. 1838 34

Ectonucleotide pyrophosphatase phosphodiesterase (ENPP1) is a positional candidate gene at chromosome 6q23 where we previously detected strong linkage with fasting-specific plasma insulin and obesity in Mexican Americans from the San Antonio Family Diabetes Study (SAFDS). We genotyped 106 single-nucleotide polymorphisms (SNPs) within ENPP1 in all 439 subjects from the linkage study, and measured association with obesity and metabolic syndrome (MS)-related traits. Of 72 polymorphic SNPs, 24 were associated, using an additive model, with at least one of eight key metabolic traits. Three traits were associated with at least four SNPs. They were high-density lipoprotein cholesterol (HDL-C), leptin, and fasting plasma glucose (FPG). HDL-C was associated with seven SNPs, of which the two most significant P values were 0.0068 and 0.0096. All SNPs and SNP combinations were analyzed for functional contribution to the traits using the Bayesian quantitative-trait nucleotide (BQTN) approach. With this SNP-prioritization analysis, HDL-C was the most strongly associated trait in a four-SNP model (P=0.00008). After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to our previous linkage peak with MS-related traits in Mexican Americans. However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations.
Obesity (Silver Spring) 2008 Jul
PMID:Association of genetic variation in ENPP1 with obesity-related phenotypes. 1846 50

The present study investigated the lipolytic (break of fat stored) effect of a citrus-based polyphenolic dietary supplement (SINETROL) at human adipocytes (ex vivo), body fat (clinical) and biochemical levels (inhibition of phosphodiesterase). Free fatty acids (FFA) release was used as indicator of human adipocyte lipolysis and SINETROL activity has been compared with known lipolytic products (isoproterenol, theopylline and caffeine). SINETROL stimulated significantly the lipolytic activity in a range of 6 fold greater than the control. Moreover, SINETROL has 2.1 greater activity than guarana 12% caffeine while its content in caffeine is 3 times lower. Clinically, two groups of 10 volunteers with BMI relevant of overweight were compared during 4 and 12 weeks with 1.4 g/day SINETROL and placebo supplementation. In the SINETROL Group the body fat (%) decreased with a significant difference of 5.53% and 15.6% after 4 and 12 weeks, respectively, while the body weight (kg) decreased with a significant difference of 2.2 and 5.2 kg after 4 and 12 weeks, respectively. These observed effects are linked to SINETROL polyphenolic composition and its resulting synergistic activity. SINETROL is a potent inhibitor of cAMP-phosphodiesterase (PDE) (97%) compared to other purified compounds (cyanidin-3 glycoside, narangin, caffeine). These results suggest that SINETROL has a strong lipolytic effect mediated by cAMP-PDE inhibition. SINETROL may serve to prevent obesity by decreasing BMI.
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PMID:Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE). 1861 77

Autotaxin catalyzes the transformation of lyso-phosphatidylcholine in lyso-phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that autotaxin is the main, if not the only source of circulating LPA. Because of its central role in pathologic conditions, such as oncology and diabetes/obesity, the biochemical properties of autotaxin has attracted a lot of attention, but confirmation of its role in pathology remains elusive. One way to validate and/or confirm its central role, is to find potent and selective inhibitors. A systematic screening of several thousand compounds using a colorimetric assay and taking advantage of the phosphodiesterase activity of autotaxin that requires the enzymatic site than for LPA generation, led to the discovery of a potent nanomolar inhibitor, [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826). This compound was inhibitory toward the various autotaxin isoforms, using an assay measuring the [(14)C]lyso-phosphatidylcholine conversion into [(14)C]LPA. We also evaluated the activity of S32826 in cellular models of diabesity and oncology. Nevertheless, the poor in vivo stability and/or bioavailability of the compound did not permit to use it in animals. S32826 is the first reported inhibitor of autotaxin with an IC(50) in the nanomolar range that can be used to validate the role of autotaxin in various pathologies in cellular models.
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PMID:S32826, a nanomolar inhibitor of autotaxin: discovery, synthesis and applications as a pharmacological tool. 1875 37

The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor mainly expressed in the central nervous system of vertebrates. Activation of the MC4R leads to a decrease in food intake, whereas inactivating mutations are a genetic cause of obesity. The binding of agouti-related protein (AGRP) reduces not only agonist-stimulated cAMP production (competitive antagonist) but also the basal activity of the receptor, as an inverse agonist. Transgenic zebrafish overexpressing AGRP display increased food intake and linear growth, indicative of a physiological role for the melanocortin system in the control of the energy balance in fish. We report on the cloning, pharmacological characterization, tissue distribution, and detailed brain mapping of a sea bass (Dicentrarchus labrax) MC4R ortholog. Sea bass MC4R is profusely expressed within food intake-controlling pathways of the fish brain. However, the activity of the melanocortin system during progressive fasting does not depend on the hypothalamic/pituitary proopiomelanocortin (POMC) and MC4R expression, which suggests that sea bass MC4R is constitutively activated and regulated by AGRP binding. We demonstrate that AGRP acts as competitive antagonist and reduces MTII-induced cAMP production. AGRP also decreases the basal activity of the receptor as an inverse agonist. This observation suggests that MC4R is constitutively active and supports the evolutionary conservation of the AGRP/MC4R interactions. The inverse agonism, but not the competitive antagonism, depends on the presence of a phosphodiesterase inhibitor (IBMX). This suggests that inverse agonism and competitive antagonism operate through different intracellular signaling pathways, a view that opens up new targets for the treatment of melanocortin-induced metabolic syndrome.
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PMID:Phosphodiesterase inhibitor-dependent inverse agonism of agouti-related protein on melanocortin 4 receptor in sea bass (Dicentrarchus labrax). 1922 41

Altered sympathetic nervous activity has been linked to the development and persistence of obesity, partly relating to overfeeding. Binding of the selective, positron-emitting phosphodiesterase-4 (PDE4) inhibitor (R)-[11C]rolipram provides a direct index of the cAMP-hydrolyzing enzyme PDE4. This study examines progressive alterations in PDE4 in a high-fat-fed obese animal model. (R)-[11C]Rolipram was injected into diet-induced obese (DIO) and diet-resistant (DR) rats; the animals were killed after 45 min, tissues were extracted, and radioactivity was quantified. Responsiveness of PDE4 to acute noradrenaline (NA) stimulation was determined by 3 h pretreatment with the NA reuptake inhibitor desipramine. There was minimal variance in caloric intake, weight gain, fasting glucose, insulin, and energy expenditure (indirect calorimetry) measures. Basal (R)-[11C]rolipram binding was comparable between DIO and DR rats at 2 or 8 weeks of feeding. The normal increase of PDE4 levels in response to elevated NA by desipramine pretreatment was ablated in PDE4-rich tissues, including brain, heart, and skeletal muscle, of DIO animals after 8 weeks of high-fat diet. Lean DR rats maintained PDE4 responsiveness indicative of a normal NA signal transduction.
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PMID:Reduced in vivo phosphodiesterase-4 response to acute noradrenaline challenge in diet-induced obese rats. 1929 60

We have found natural products exhibiting lipolysis-promoting activity in subcutaneous adipocytes, which are less sensitive to hormones than visceral adipocytes. The activities and a action mechanisms of a novel plant extract of Cirsium oligophyllum (CE) were investigated in isolated adipocytes from rat subcutaneous fat, and its fat-reducing effects by peroral administration and topical application were evaluated in vivo. CE-induced lipolysis was synergistically enhanced by caffeine, a phosphodiesterase inhibitor, and was reduced by propranolol, a beta adrenergic antagonist. The peroral administration of 10% CE solution to Wistar rats for 32 days reduced body weight gain, subcutaneous, and visceral fat weights by 6.6, 26.2, and 3.0%, respectively, as compared to the control group. By the topical application of 2% of this extract to rats for 7 days, weight of subcutaneous fat in the treated skin was reduced by 23.2%. This fat mass reduction was accompanied by the up-regulation of uncoupling protein 1 (UCP), a principal thermogenic mitochondrial molecule related to energy dissipating, in subcutaneous fat and UCP3 in skin except for the fat layer. These results indicate that CE promotes lipolysis via a mechanism involving the beta adrenergic receptor, and affects the body fat mass. This fat reduction may be partially due to UCP up-regulation in the skin including subcutaneous fat. This is the first report showing that repeated lipolysis promotion through CE administration may be beneficial for the systematic suppression of body fat accumulation or the control of fat distribution in obesity.
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PMID:Body fat mass reduction and up-regulation of uncoupling protein by novel lipolysis-promoting plant extract. 1942 41


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