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)

17Beta-estradiol (E(2)) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E(2) on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E(2) inhibited 11beta-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E(2) on 11beta-HSD1 activity was observed within 5-10 min. Furthermore, acetylation or alpha-epimerization of 17-hydroxy group of E(2) attenuated the inhibitory effect on 11beta-HSD1. These results indicate that the inhibition of 11beta-HSD1 by E(2) depends on neither an ER-dependent route, transcriptional pathway nor non-specific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11beta-HSD1, was unaffected by E(2). A kinetic study revealed that E(2) acted as a non-competitive inhibitor of 11beta-HSD1. The inhibitory effect of E(2) on 11beta-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E(2) inhibits 11beta-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.
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PMID:17Beta-estradiol inhibits 11beta-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes. 1938 Apr 58

Elevated cortisol concentrations have been associated with metabolic diseases such as diabetes type 2 and obesity. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, catalyzing the conversion of inactive 11-ketoglucocorticoids into their active 11beta-hydroxy forms, plays an important role in the regulation of cortisol levels within specific tissues. The selective inhibition of 11beta-HSD1 is currently considered as promising therapeutic strategy for the treatment of metabolic diseases. In recent years, natural compound-derived drug design has gained considerable interest. 18beta-glycyrrhetinic acid (GA), a metabolite of the natural product glycyrrhizin, is not selective and inhibits both 11beta-HSD1 and 11beta-HSD2. Here, we compare the biological activity of 18beta-GA and its diastereomer 18alpha-GA against the two enzymes in lysates of transfected HEK-293 cells and show that 18alpha-GA selectively inhibits 11beta-HSD1 but not 11beta-HSD2. This is in contrast to 18beta-GA, which preferentially inhibits 11beta-HSD2. Using a pharmacophore model based on the crystal structure of the GA-derivative carbenoxolone in complex with human 11beta-HSD1, we provide an explanation for the differences in the activities of 18alpha-GA and 18beta-GA. This model will be used to design novel selective derivatives of GA.
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PMID:Selective inhibition of 11beta-hydroxysteroid dehydrogenase 1 by 18alpha-glycyrrhetinic acid but not 18beta-glycyrrhetinic acid. 1942 29

Obese individuals with fat stored in visceral adipose tissue (VAT) generally suffer greater adverse metabolic consequences than those with fat stored predominantly in subcutaneous adipose tissue (SAT), but its molecular basis is not completely understood. We isolated paired samples of SAT and VAT from 15 lean and 15 obese subjects and systematically compared the transcription level of genes that may determine fat distribution and metabolic sequelae between SAT and VAT using quantitative real-time PCR. We found that, leptin levels were lower in VAT than SAT, for both lean and obese subjects. In lean subjects, tumor necrosis factor-alpha (TNF-alpha) was expressed equally in both fat depots, while toll-like receptor 4 (TLR4) and glucocorticoid receptor (GR) showed significantly lower expression in VAT than SAT. In obese subjects, TNF-alpha and TLR4 expression were significantly higher in VAT than SAT, yet GR expression did not differ in these areas. For all subjects, VAT 11beta-hydroxysteroid dehydrogenate type 1 (11beta-HSD1) level was significantly correlated with BMI. GR expression level was significantly correlated with TLR4 expression level. Cultured adipocytes showed higher TLR4 mRNA level after differentiation, and higher TNF-alpha level after treatment with free fatty acids. These results suggest that there are depot-specific differences in leptin, TNF-alpha, TLR4 and GR transcriptions in humans. TLR4 signaling and higher 11beta-HSD1 and GR levels in VAT may contribute predominantly to inflammatory factor production and subsequent metabolic sequelae in obese human.
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PMID:Comparison of gene transcription between subcutaneous and visceral adipose tissue in Chinese adults. 1956 4

PPARgamma and 11beta-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPARgamma agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11beta-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of alpha-aryloxy-alpha-methylhydrocinnamic acids as dual functional agents which activate PPARgamma and inhibit 11beta-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPARgamma (EC(50)=6.76 microM) and 11beta-HSD1 (IC(50)=0.76 microM) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile.
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PMID:Discovery of novel dual functional agent as PPARgamma agonist and 11beta-HSD1 inhibitor for the treatment of diabetes. 1957 56

Cortisol has wide-ranging actions, namely in gluconeogenesis and glycogenesis and exerts its effects through the glucocorticoid receptor. In the present study, we examined effects of glucocorticoid receptor blockade on type 2 diabetes control using the antagonist, RU486. Obese diabetic mice received daily injections of vehicle or RU486 over 28 days. Food intake, body weight, and plasma glucose were measured frequently. At 28 days, glucose tolerance, insulin sensitivity, and plasma triglycerides were assessed. Epididymal white adipose tissue and liver were excised for measurement of gene expression. Daily administration of RU486 had no effect on body weight or food intake, but plasma glucose concentrations were significantly lowered (1.4-1.6-fold; p<0.05 to p<0.001). Glucose concentrations were also significantly reduced (2.2-fold; p<0.001) following a glucose challenge. Similarly, exogenous insulin evoked a significantly greater reduction in plasma glucose (3.6-fold; p<0.01). Gene expression analysis revealed a significant reduction in hepatic mRNA of key enzymes, namely PEPCK-C (25%; p<0.01) and G6 Pase (32%; p<0.01) and also 11beta-HSD1 (18%; p<0.05). Investigation of adipose tissue gene expression also demonstrated reduced expression in 11beta-HSD1 (47%; p<0.05) and LPL (47%; p<0.001). These data demonstrate wide-ranging effects of glucocorticoid receptor antagonism on gene expression and metabolism, illustrating the therapeutic potential of specific glucocorticoid receptor antagonists in obesity-related diabetes.
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PMID:Effect of RU486 on hepatic and adipocyte gene expression improves diabetes control in obesity-type 2 diabetes. 1967 Jan 52

Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.
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PMID:Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model. 1967 66

The metabolic abnormalities found associated with high blood glucocorticoid levels (e.g. rare Cushing's syndrome) include insulin-resistance, visceral obesity, hypertension, dyslipidaemia and an increased risk of cardiovascular diseases. The same constellation of abnormalities is found in the highly prevalent idiopathic obesity/insulin-resistance (metabolic)-syndrome. It is now apparent that tissue-specific changes in cortisol metabolism explain these parallels rather than altered blood cortisol levels. Primary among these changes is increased intracellular glucocorticoid reactivation, catalysed by the enzyme 11beta-hydroxysteroid dehydrogenase type (HSD)-1 in obese adipose tissue. Liver, skeletal muscle, endocrine pancreas, blood vessels and leukocytes express 11beta-HSD1 and their potential role in metabolic disease is discussed. The weight of evidence, much of it gained from animal models, suggests that therapeutic inhibition of 11beta-HSD1 will be beneficial in most cellular contexts, with clinical trials supportive of this concept.
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PMID:Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. 1980 14

Regeneration of active glucocorticoids within liver and adipose tissue by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) may be of pathophysiological importance in obesity and metabolic syndrome and is a therapeutic target in type 2 diabetes. Polymorphisms in HSD11B1, the gene encoding 11 beta-HSD1, have been associated with metabolic phenotype in humans, including type 2 diabetes and hypertension. Here, we have tested the functional consequences of two single nucleotide polymorphisms located in contexts that potentially affect tissue levels of 11 beta-HSD1. We report no effect of allelic variation at rs846910, a polymorphism within the 5'-flanking region of the gene on HSD11B1 promoter activity in vitro. However, compared with the common G allele, the A allele of rs13306421, a polymorphism located two nucleotides 5' to the translation initiation site, gave higher 11 beta-HSD1 expression and activity in vitro and was translated at higher levels in in vitro translation reactions, possibly associated with a lower frequency of "leaky scanning." These data suggest that this polymorphism may have direct functional consequences on levels of 11 beta-HSD1 enzyme activity in vivo. However, the rs13306421 A sequence variant originally reported in other ethnic groups may be of low prevalence because it was not detected in a population of 600 European Caucasian women.
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PMID:Functional effects of polymorphisms in the human gene encoding 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1): a sequence variant at the translation start of 11 beta-HSD1 alters enzyme levels. 1993 76

Systemic glucocorticoid excess, as exemplified by the Cushing syndrome, leads to obesity and all further symptoms of the metabolic syndrome. The current obesity epidemic, however, is not characterized by increased plasma cortisol concentrations, but instead comes along with chronic low-grade inflammation in adipose tissue and concomitant increased levels of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1, gene HSD11B1), a parameter known to cause obesity in a mouse model. 11beta-HSD1 represents an intracellular amplifier of active glucocorticoid, thus enhances the associated effects on the inflammatory response as well as on nutrient and energy metabolism, and may therefore cause and exacerbate obesity by local increase of glucocorticoid concentrations. Obtained by extensive literature and database searching, the present review includes comprehensive lists of primary glucocorticoid-sensitive genes and gene products as well as of the thus far known regulators of HSD11B1 expression with implication in inflammation and metabolic disease. Collectively, the data clearly show that, in addition to amplifying active glucocorticoid and thus profoundly modulating inflammation and nutrient metabolism, 11beta-HSD1 is subject to tight control of multiple additional immunomodulatory and metabolic regulators. Hence, 11beta-HSD1 acts at the interface of inflammation and obesity and represents an efficient integrator and effector of local inflammatory and metabolic state.
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PMID:11beta-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. 2004 52

Tissue glucocorticoid levels in the liver and adipose tissue are regulated by regeneration of inactive glucocorticoid by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) and inactivation by 5alpha- and 5beta-reductases. A low carbohydrate diet increases hepatic 11beta-HSD1 and reduces glucocorticoid metabolism during weight loss in obese humans. We hypothesized that similar variations in macronutrient proportions regulate glucocorticoid metabolism in obese rats. Male Lister Hooded rats were fed an obesity-inducing ad libitum 'Western' diet (37% fat, n = 36) for 22 weeks, then randomised to continue this diet (n = 12) or to switch to either a low carbohydrate (n = 12) or a moderate carbohydrate (n = 12) diet for the final 8 weeks. A parallel lean control group were fed an ad libitum control diet (10% fat, n = 12) throughout. The low and moderate carbohydrate diets decreased hepatic 11beta-HSD1 mRNA compared with the Western diet (both 0.7+/-0.0 vs 0.9+/-0.1 AU; p<0.01), but did not alter 11beta-HSD1 in adipose tissue. 5Alpha-reductase mRNA was increased on the low carbohydrate compared with the moderate carbohydrate diet. Compared with lean controls, the Western diet decreased 11beta-HSD1 activity (1.6+/-0.1 vs 2.8+/-0.1 nmol/mcg protein/hr; p<0.001) and increased 5alpha-reductase and 5beta-reductase mRNAs (1.9+/-0.3 vs 1.0+/-0.2 and 1.6+/-0.1 vs 1.0+/-0.1 AU respectively; p<0.01) in the liver, and reduced 11beta-HSD1 mRNA and activity (both p<0.01) in adipose tissue. Although an obesity-inducing high fat diet in rats recapitulates the abnormal glucocorticoid metabolism associated with human obesity in liver (but not in adipose tissue), a low carbohydrate diet does not increase hepatic 11beta-HSD1 in obese rats as occurs in humans.
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PMID:Effects of proportions of dietary macronutrients on glucocorticoid metabolism in diet-induced obesity in rats. 2009 42


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