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

To achieve a better understanding of the biochemical basis of obesity, we have undertaken comparative analyses of adipose tissue of lean and obese mice. By two-dimensional gel analysis, carbonic anhydrase-III (CA III) has been identified as a major constituent of murine adipose tissue. Quantitative comparisons of CA III protein and mRNA levels indicate that this enzyme is expressed at lower levels in adipose tissue from animals that were either genetically obese or had experimentally induced obesity compared to levels in the corresponding lean controls. This decrease in CA III expression was unique to adipose tissue, since other CA III-containing organs and tissues did not show a change when lean and obese animals were compared. Additionally, levels of CA III in adipose tissue from obese animals responded to acute changes in energy balance of the animal. These results are discussed in light of possible metabolic roles for CA III.
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PMID:Expression of CA III in rodent models of obesity. 192

Six grossly obese patients were fed 5000 calorie diets for 4 wk. During one period of 2 wk, the calories were consumed over 4 hr (gorging) and during the other 2 wk, the dietary intake was spread over 20 hr (nibbling). Each of these periods followed a low caloric intake which lasted at least 10 days. Three male patients (group I) were studied at or near their maximal weight and three females (group II) after a weight loss of 50-70 kg. The patients in group II gained more weight than those in group I. Lipogenesis from pyruvate was greater in group II than in group I. Rapid ingestion of food (gorging) was accompanied by a significant increase in glyceride-glycerol-(14)C and fatty acids-(14)C from pyruvate-(14)C. The enzymatic activity of sn-glycerol 3-phosphate dehydrogenase and mitochondrial glycerophosphate oxidase paralleled the rate of formation of glyceride-glycerol. Lipogenesis from pyruvate was significantly lower when the bicarbonate concentration was reduced from 25 to 10 mM. Citrate and acetate were also converted to fatty acids but there was no difference between gorging and nibbling. An inhibitor of carbonic anhydrase significantly reduced the conversion of pyruvate into CO(2), glyceride-glycerol, and fatty acids. These data on gorging and nibbling have been related to other studies suggesting that the frequency of food intake may be inversely related to obesity.
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PMID:Lipogenesis in human adipose tissue: some effects of nibbling and gorging. 501 Oct 99

Proteins from 5- to 7-wk-old lean and obese Zucker rats were separated by one-dimensional sodium dodecyl sulfate (SDS) and two-dimensional SDS-isoelectric focusing-polyacrylamide gel electrophoresis. Laser densitometry revealed an obesity-related decrease in the concentration of a 28-kDa cytosolic adipocyte protein, the most abundant protein in adipocytes from lean Zucker rats. Microsequencing revealed the identity of this protein to be carbonic anhydrase III (CA III). The identity and obesity-related decrease was further confirmed using isoform-specific antisera and CA III enzyme activity measurements made by 18O mass spectrometry. Immunoblotting studies also revealed that CA III is present in at least two charge isoforms in adipocytes. Our data indicate that lean Zucker rat adipocytes may represent the richest source of CA III in nature (24% of the cytosolic protein content). An obesity-related decrease in both the concentration and activity of CA III was observed in two lipogenic tissues, liver and white fat, but not in soleus muscle. Adipocyte CA III activity was no longer depressed when hyperinsulinemic obese rats were made insulin deficient by streptozotocin injection. This suggests that the obesity-related decrease in CA III may be related to the hyperinsulinemia as well as to the insulin hyperresponsiveness that adipocytes from obese Zucker rats of this age display.
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PMID:Carbonic anhydrase III in obese Zucker rats. 847 41

The first inhibition study of the mitochondrial isozyme carbonic anhydrase (CA) V (of murine origin) with a series of aromatic and heterocyclic sulfonamides is reported. Inhibition data of the cytosolic isozymes CA I and CA II and the membrane-bound isozyme CA IV with these inhibitors are also provided for comparison. Several low nanomolar CA V inhibitors were detected (KI values in the range of 4-15 nM), most of them belonging to the acylated sulfanilamide, ureido-benzenesulfonamide, 1,3,4-thiadiazole-2-sulfonamide, and aminobenzolamide type of compounds. The clinically used inhibitors acetazolamide, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and topiramate on the other hand were less effective CA V inhibitors, showing inhibition constants in the range of 47-63 nM. Some of the investigated sulfonamides, such as the ureido-benzenesulfonamides and the acylated sulfanilamides showed higher affinity for CA V than for the other isozymes, CA II included, which is a remarkable result, since most compounds investigated up to now inhibited the cytosolic isozyme CA II better. These results prompt us to hypothesize that the selective inhibition of CA V, or the dual inhibition of CA II and CA V, may lead to the development of novel pharmacological applications for such sulfonamides, for example in the treatment or prevention of obesity, by inhibiting CA-mediated lipogenetic processes.
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PMID:Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides. 1497 7

It is well known that the role of leptin in the body is to regulate food intake and energy expenditure but the process of leptin secretion by adipose tissue and the components involved in this process are still obscure. Carbonic anhydrase III (CA III) is the most abundant protein of the rat adipose tissue and its amount decreases with obesity. The effect of the inhibition of CA III on leptin secretion by rat epididymal adipose tissue was examined. Dorzolamide, a CA inhibitor, caused a decrease in dexamethasone and insulin-induced leptin secretion suggesting a possible role for CA III in the mechanism of leptin secretion.
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PMID:The effect of carbonic anhydrase inhibition on leptin secretion by rat adipose tissue. 1544 34

Among the 14 human isozymes of carbonic anhydrase (CA, EC 4.2.1.1) presently known, the cytosolic hCA II is the most active and plays a host of physiological functions, whereas the mitochondrial hCA V is unique due to its role in several biosynthetic reactions. An inhibition study of these isozymes with a series of sulfonamides is reported here, with the scope to detect lead molecules for the design of isozyme-specific CA inhibitors (CAIs) targeting the mitochondrial isoform. Indeed, recently it has been shown that CA V is a novel target for the drug design of anti-obesity agents among others. Compounds included in this study were mainly ortho-, meta-, and para-substituted-benzenesulfonamides, together with several halogeno-substituted sulfanilamides and disubstituted-benzene-1,3-disulfonamide derivatives. Isozyme V showed an inhibition profile with these sulfonamides different of that of hCA II. Thus, IC(50) values in the range of 80 nM to 74 microM against hCA II, and 0.78-63.7 microM against hCA V with these derivatives have been obtained. Only one compound, 2-carboxymethyl-benzenesulfonamide, was more active against hCA V over hCA II (selectivity ratio of 1.39), whereas all other derivatives investigated here were much better hCA II inhibitors (selectivity ratios CA II/CA V in the range of 0.0008-0.73) than hCA V inhibitors.
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PMID:Carbonic anhydrase inhibitors: inhibition of human cytosolic isozyme II and mitochondrial isozyme V with a series of benzene sulfonamide derivatives. 1548 52

Studies on the biochemical and molecular mechanisms underlying obesity have shown that the expression of some proteins was decreased with obesity in rat adipose tissue. One of these proteins is carbonic anhydrase III (CA III) which constitutes 24% of the cytosolic protein content and its function is unclear. A freshly isolated rat adipose cell culture model was used to examine the effect of leptin and insulin on CA III expression. It was found that leptin decreased CA III expression while insulin increased it which suggests that the decrease in CA III expression observed in obesity in rat adipose tissue may be related to hyperleptinemia.
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PMID:Effects of leptin and insulin on CA III expression in rat adipose tissue. 1550 1

An inhibition study of the human cytosolic isozymes I, and II, the mitochondrial isoform VA, and the tumor-associated, transmembrane isozyme IX of carbonic anhydrase (CA, EC 4.2.1.1) with a library of aromatic/heteroaromatic/polycyclic difluoromethanesulfonamides is reported. Most of the inhibitors were derivatives of benzenedifluoromethanesulfonamide incorporating substituted-phenyl moieties, or were methylsulfonamide and difluoromethyl-sulfonamide derivatives of the sulfamates COUMATE and EMATE, respectively. Except for the methylsulfonamide-COUMATE derivative which behaved as a potent CA II inhibitor (K(I) of 32nM), these sulfonamides were moderate inhibitors of all isozymes, with inhibition constants in the range of 96-5200nM against hCA I, of 80-670nM against hCA II, and of 195-9280nM against hCA IX, respectively. Remarkably, some derivatives, such as 3-bromophenyl-difluoromethanesulfonamide, showed a trend to selectively inhibit the mitochondrial isoform CA VA, showing selectivity ratios for inhibiting CA VA over CA II of 3.53; over CA I of 6.84 and over CA IX of 9.34, respectively, although it is a moderate inhibitor (K(I) of 160nM). Some of these derivatives may be considered as leads for the design of isozyme selective CA inhibitors targeting the mitochondrial isozyme CA VA, with potential use as anti-obesity agents.
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PMID:Carbonic anhydrase inhibitors: inhibition of the human isozymes I, II, VA, and IX with a library of substituted difluoromethanesulfonamides. 1620 42

The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous zinc enzymes which catalyze a very simple physiological reaction, the interconversion between carbon dioxide and the bicarbonate ion, and are involved in physiological and pathological processes. The different isozymes have been considered as important targets for inhibitors with clinical applications. Several sulfonamide carbonic anhydrase inhibitors (CAIs) were used for decades as diuretics, anti-glaucoma, anti-epileptic, anti-ulcer agents, or as drugs for treating other neurological/neuromuscular disorders, whereas presently several such agents still find wide applications in therapy, mainly as topically acting anti-glaucoma drugs, anti-cancer, or anti-obesity agents. Although sulfonamides were considered the moiety par excellence to coordinate the catalytic zinc and for designing potent CAIs, in recent years related functional groups such as sulfamate, sulfamide and others have proven to be successful in the design of selective CAIs. The present review will deal with these different zinc binding functions recently reported in literature.
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PMID:New zinc binding motifs in the design of selective carbonic anhydrase inhibitors. 1691 98

A 3D QSAR selectivity analysis of carbonic anhydrase (CA) inhibitors using a data set of 87 CA inhibitors is reported. After ligand minimization in the binding pockets of CA I, CA II, and CA IV isoforms, selectivity CoMFA and CoMSIA 3D QSAR models have been derived by taking the affinity differences (DeltapKi) with respect to two CA isozymes as independent variables. Evaluation of the developed 3D QSAR selectivity models allows us to determine amino acids in the respective CA isozymes that possibly play a crucial role for selective inhibition of these isozymes. We further combined the ligand-based 3D QSAR models with the docking program AUTODOCK in order to screen for novel CA inhibitors. Correct binding modes are predicted for various CA inhibitors with respect to known crystal structures. Furthermore, in combination with the developed 3D QSAR models we could successfully estimate the affinity of CA inhibitors even in cases where the applied scoring function failed. This novel strategy to combine AUTODOCK poses with CoMFA/CoMSIA 3D QSAR models can be used as a guideline to assess the relevance of generated binding modes and to accurately predict the binding affinity of newly designed CA inhibitors that could play a crucial role in the treatment of pathologies such as tumors, obesity, or glaucoma.
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PMID:3D QSAR selectivity analyses of carbonic anhydrase inhibitors: insights for the design of isozyme selective inhibitors. 1712 13


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