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

There are striking similarities between Cushing's syndrome and the 'metabolic syndrome X' since both are characterised by hypertension, insulin resistance, glucose intolerance, hyperlipidaemia, and central obesity. The possibility that cortisol contributes to the associations between multiple risk factors for cardiovascular disease was rejected when it was demonstrated that there was no elevation in cortisol secretion or circulating concentration in patients with essential hypertension or type 2 diabetes mellitus. However, in recent years the enormous variability in tissue sensitivity to cortisol has become apparent. We have measured tissue sensitivity to glucocorticoids using an assay of skin vasoconstriction and have demonstrated its relationship with high blood pressure, insulin resistance, glucose intolerance, and hypertriglyceridaemia. Our data suggest that the increase in dermal glucocorticoid sensitivity is not a secondary phenomenon and may be explained by increased glucocorticoid receptor affinity together with impaired inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase. Importantly, we have not found that enhanced peripheral glucocorticoid sensitivity is associated with compensatory suppression of cortisol secretion, so that the maintenance of normal circulating cortisol concentrations in patients with cardiovascular risk factors may be paradoxical and inappropriate.
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PMID:Abnormal glucocorticoid activity in subjects with risk factors for cardiovascular disease. 896 30

For a given body mass index (BMI), mortality is higher in patients with central compared to generalized obesity. Glucocorticoids play an important role in determining body fat distribution, but circulating cortisol concentrations are reported to be normal in obese patients. Our recent studies show enhanced conversion of inactive cortisone (E) to active cortisol (F) through the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in cultured omental adipose stromal cells; the autocrine production of F may be a crucial factor in the pathogenesis of central obesity. We have now analyzed F metabolism in subjects with BMIs between 20-25 kg/m2 (group A), 25-30 kg/m2 (group B), and more than 30 kg/m2 (group C; n 12 in each group; six males and six premenopausal females; aged 23-44 yr). Glucose/insulin were measured using a 75-g oral glucose tolerance test, and each subject had total body and regional fat (scapular, waist, hip, and thigh) quantified using dual energy x-ray absorptiometry. Urinary total F metabolites (measured by gas chromatography/mass spectrometry) were increased in subjects with obesity [group A, 11,176 +/- 1,530 microg/24 h (mean +/- SE); group C, 13,661 +/- 1,444], although not significantly so (P = 0.08). There was a significant reduction in the urinary tetrahydrocortisol (THF) +/- 5alpha-THF/tetrahydrocortisone (THE) and the cortol/cortolone ratio in obesity (group A vs. C, 1.06 +/- 0.08 vs. 0.84 +/- 0.04 and 0.41 +/- 0.03 vs. 0.34 +/- 0.03, respectively; both P < 0.05). Urinary free F (UFF) excretion was similar in all three groups, as was the UFF/urinary free E (UFE) ratio. The 0900 h circulating F, E, and ACTH pre- and postovernight 1-mg dexamethasone suppression values were similar in all three groups, but a reduction in the generation of serum F from dexamethasone-suppressed values after oral cortisone acetate (25 mg) was evident in both obese groups [e.g. 546 +/- 37 nmol/L in group A vs. 412 +/- 40 in group B (P < 0.05) and 388 +/- 38 in group C (P < 0.01) 180 min post-E]. Insulin resistance was present in groups B and C, but regression analysis revealed no relationship between F metabolites or the THF +/- 5alpha-THF/THE ratio and insulin action (homeostasis model assessment analysis and insulin values in the oral glucose tolerance test). There was, however, a highly significant relationship between the THF +/- 5alpha-THF/THE ratio and BMI (t = -3.44; P < 0.01) and total body fat (t = -2.27; P < 0.05). Stepwise regression analyses indicated an inverse relationship between THF+/-5alpha-THF/THE and scapular and waist fat (t = -2.25; P = 0.03) and a direct relationship with hip and thigh fat (t = 2.42; P = 0.02) in both sexes. The fall in the THF + 5alpha-THF/THE ratio but unchanged UFF/UFE ratio together with impaired F concentrations after oral E indicates inhibition of 11betaHSD1 in subjects with obesity. This results in an increased MCR for F, explaining the increased F secretion rate in obesity in the face of normal circulating F concentrations. 11BetaHSD1 activity is highly related to body fat distribution, with android or central obesity, but not gynoid obesity, associated with reduced activity in both sexes. This reduction in 11betaHSD1 activity raises new questions as to the primary role of 11betaHSD1 in the pathogenesis of insulin resistance and central obesity.
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PMID:Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity. 1008 90

Glucocorticoids play an important role in determining adipose tissue distribution and function, with glucocorticoid excess states such as Cushing's syndrome resulting in central obesity. We have investigated the functional significance of local generation of cortisol within adipose tissue from inactive cortisone through the activity of the NADP(H)-dependent enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). In primary cultures of paired omental (om) and sc human adipose stromal cells (ASC; n = 34), 11betaHSD1 oxo-reductase activity was significantly higher in om ASC (median, 40.2 pmol/mg protein x h; 95% confidence interval, 1.8-105) compared with sc ASC (median, 11.4; 95% confidence interval, 0-48.1; P<0.001) despite similar endogenous NADPH/NADP concentrations. Both cortisol and insulin increased the differentiation of ASC to adipocytes (as assessed by glycerol-3-phosphate dehydrogenase expression), but only cortisol increased 11betaHSD1 activity and messenger RNA levels in a dose-dependent fashion. Cortisone (500 nM) was as effective as 500 nM cortisol in inducing ASC differentiation, but this stimulatory effect was inhibited by coincubation with the 11betaHSD1 inhibitor, glycyrrhetinic acid. The higher local conversion of cortisone to active cortisol through expression of 11betaHSD1 in om compared with sc ASC may explain the specific action of glucocorticoids on different adipose tissue depots. 11betaHSD1 expression in om ASC is regulated at a transcriptional level and is increased by glucocorticoids, but is not entirely dependent upon ASC differentiation. Inhibition of 11betaHSD1 within om ASC inhibits cortisone-induced ASC differentiation. These findings indicate that local metabolism of glucocorticoid may control differentiation of adipose tissue in a site-specific fashion. Specific inhibitors of 11betaHSD1 may offer a novel approach for the treatment of patients with central obesity.
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PMID:Differentiation of adipose stromal cells: the roles of glucocorticoids and 11beta-hydroxysteroid dehydrogenase. 1038 14

Obesity is frequently associated with insulin-resistance and abnormal glucose homeostasis. Recent evidence indicates that TNFalpha may play a role in mediating the insulin-resistance of obesity through its overexpression in adipose tissue. Previously, we have shown that human adipose stromal cells contain 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity. The present study was designed to examine the effects of insulin on 11beta-HSD1 expression in human adipose stromal cells under basal and TNFalpha-stimulated conditions. The cells were obtained from breast adipose tissue by collagenase digestion, and grown to confluence under replicating conditions in 10% fetal bovine serum. The cells were transferred to serum-free medium for 24 h prior to treatment with either TNFalpha, insulin or both for a further 24 h. The level of 11beta-HSD1 reductase activity was determined by measuring the conversion of [(3)H]-cortisone to [(3)H]-cortisol at a substrate concentration of 10 nM. Treatment with TNFalpha at concentrations of 0.1-10 ng/ml resulted in a dose dependent increase in 11beta-HSD1 reductase activity from 1.5 to 10-fold. Insulin (0.1-100 nM) had no effect under basal conditions, but inhibited the stimulatory effects of TNFalpha (5 ng/ml) on 11beta-HSD1 reductase activity in a dose dependent fashion (8-66%) inhibition). Northern blot analysis revealed corresponding changes in the level of 11beta-HSD1 mRNA, suggesting that the effects of TNFalpha and insulin on 11beta-HSD1 activity are mediated at the level of gene transcription. The interaction between insulin and TNFalpha suggests that local and systemic factors may act in a concerted fashion to modulate glucocorticoid activity in adipose and other peripheral tissues.
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PMID:Insulin attenuates the stimulatory effects of tumor necrosis factor alpha on 11beta-hydroxysteroid dehydrogenase 1 in human adipose stromal cells. 1077 8

Childhood obesity is accompanied by a variety of cardiovascular risk factors (hypertension, insulin resistance, dyslipidaemia) which tend to aggregate (syndrome X). 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is supposed to play a role in the pathogenesis of hypertension and the development of syndrome X. There are two isoforms of 11beta-HSD. 11beta-HSD-2 is responsible for the inactivation of cortisol to inactive cortisone. In the case of impaired enzyme activity the ratio of urinary tetrahydrocortisol (THF)+ its isomer allotetrahydrocortisol (5alpha-THF)/tetrahydrocortisone (THE) is elevated. 11beta-HSD-1 is an oxo-reductase, which type catalyses the conversion of cortisone to cortisol. The aim of the present study was to investigate if there was any alteration in the urinary cortisol metabolites reflecting 11beta-HSD activity in hypertensive obese children (no.=15) as compared to normotensive obese (no.=11) and normotensive non-obese children (no.=15). We found an increased excretion of cortisol metabolites in hypertensive obese children compared to obese and normal - weight children having normal blood pressure. The ratio of THF+5alpha(THF/THE had a significant correlation with systolic blood pressure. On the basis of our study the ratio of THF+5alpha-THF/ THE reflecting on altered enzyme activity seems to be an independent factor influencing especially systolic blood pressure in hypertensive obese children.
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PMID:Urinary cortisol to cortisone metabolites in hypertensive obese children. 1100 67

Obesity has been associated with alterations in glucocorticoid metabolism in both man and rodents, but the underlying mechanisms remain undefined. We have previously reported tissue-specific alterations in 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) in obese Zucker rats predicting that reactivation of corticosterone is decreased in liver but increased in omental fat. The mechanisms of dysregulation of 11 beta-HSD1 in obesity are not known, and in this study we have investigated the potential role of glucocorticoids and insulin. In one experiment lean and obese Zucker rats were adrenalectomised, and in a second experiment they were sensitised to insulin by treatment with either metformin or rosiglitazone. Adrenalectomy (ADX) of obese animals attenuated weight gain, normalised hepatic 11 beta-HSD1 kinetics by an effect on V(max) (V(max)in sham-operated animals, 6.6+/-1.1 nmol/min per mg in lean vs 3.4+/-0.6 in obese, P<0.01; in ADX animals 5.9+/-1.1 in lean vs 6.9+/-1.8 in obese, NS), and reversed the difference in omental fat 11 beta-HSD1 activity (18.9+/-4.2% in lean ADX vs 8.2+/-2.3 in obese ADX, P=0.03). Both metformin and rosiglitazone improved insulin sensitivity in obese, but not lean animals, and had no effect on 11 beta-HSD1 activity in either liver or fat. However, both treatments normalised adrenal hypertrophy in obese animals (48+/-29 mg in obese vehicle vs 37+/-1.2 in metformin and 38+/-1.8 in rosiglitazone treated, both P<0.01), and rosiglitazone tended to attenuate hypercorticosteronaemia in obese rats. Neither treatment attenuated weight gain; in fact, weight gain was enhanced by rosiglitazone in obese rats. In summary, altered 11 beta-HSD1 activity in obese Zucker rats is reversible following adrenalectomy, but the mechanism is unclear since adrenalectomy also normalises many other metabolic abnormalities. The current study suggests that hyperinsulinaemia is not responsible for tissue-specific dysregulation of 11 beta-HSD1. However, insulin sensitisation did reverse adrenal hypertrophy, suggesting that hyperinsulinaemia may be a key factor contributing to activation of the hypothalamic- pituitary-adrenal (HPA) axis in obesity independently of tissue-specific changes in 11 beta-HSD1.
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PMID:Mechanisms of dysregulation of 11 beta-hydroxysteroid dehydrogenase type 1 in obese Zucker rats. 1111 81

Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local prereceptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In obese Zucker rats 11beta-HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin insensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from 16 participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r = 0.47, p < 0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r = 0.43, p < 0.02), and converted less cortisone to cortisol after oral administration (r = 0.49, p < 0.01), suggesting impaired hepatic 11beta-HSD1 activity. By contrast, in vitro 11beta-HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r = 0.66, p < 0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11beta-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11beta-HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.
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PMID:Tissue-specific dysregulation of cortisol metabolism in human obesity. 1123 41

In the insulin resistance (IR) syndrome, sex-specific differences have been reported. First, hypertension more often correlates with hyperinsulinemia in women than in men with the IR syndrome. In addition, salt sensitivity of blood pressure appears to be independent of the activity of the renin-angiotensin system in women, whereas in men there is a strong correlation between the two variables. Secondly, the dyslipidemia found in women with the IR syndrome is characterized by less postprandial plasma insulin, triglycerides, and fatty acid response to a standardized meal. However, this sex difference in lipids disappears after correction for visceral fat mass. Fat physiology and biochemistry differ between the two sexes. In women, adipose cells express less glucocorticoid receptors and less 11beta-hydroxysteroid dehydrogenase. In women visceral fat accumulation appears to be a constant feature of the IR syndrome but in men the syndrome can be present without central obesity. Lastly, during the reproductive years of women, the IR syndrome, such as in pre-eclampsia, may cause fetal growth retardation that has been proposed together with maternal malnutrition to be at the origin of the increased risk for impaired glucose tolerance, hyperinsulinemia, and hypertension in adult life. This gives yet another dimension to this disease in women since in essence they may ultimately transmit this syndrome to both sexes.
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PMID:Sex-related differences in the insulin resistance syndrome. 1127 93

Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested that the increased activity and expression of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) generating active cortisol from cortisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal cells (ASC) were used as in vitro models to investigate the tissue-specific regulation of 11betaHSD1 expression and activity. Treatment with tumor necrosis factor-alpha (TNFalpha) caused a dose-dependent increase in 11betaHSD1 activity in primary cultures of both sc [1743.1 +/- 1015.4% (TNFalpha, 10 ng/ml); P < 0.05 vs. control (100%)] and omental [375.8 +/- 57.0% (TNFalpha, 10 ng/ml); P < 0.01 vs. control (100%)] ASC, but had no effect on activity in human hepatocytes [90.2 +/- 2.8% (TNFalpha, 10 ng/ml); P = NS vs. control (100%)]. Insulin-like growth factor I (IGF-I) caused a dose-dependent inhibition of 11betaHSD1 activity in sc [49.7 +/- 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [71.6 +/- 7.5 (IGF-I, 100 ng/ml); P < 0.01 vs. control (100%)] stromal cells, but not in human hepatocytes [101.8 +/- 15.7% (IGF-I, 100 ng/ml); P = NS vs. control (100%)]. Leptin treatment did not alter 11betaHSD1 activity in human hepatocytes, but increased activity in omental ASC [135.8 +/- 14.1% (leptin, 100 ng/ml); P = 0.08 vs. control (100%)]. Treatment with interleukin-1beta induced 11betaHSD1 activity and expression in sc and omental ASC in a time- and dose-dependent manner. 15-Deoxy-12,14-PGJ2, the putative endogenous ligand of the orphan nuclear receptor peroxisome proliferator-gamma, significantly increased 11betaHSD1 activity in omental cells [179.7 +/- 29.6% (1 microM); P < 0.05 vs. control (100%)] and sc [185.3 +/- 12.6% (1 microM); P < 0.01 vs. control (100%)] ASC, and it is possible that expression of this ligand may ensure continued cortisol generation to permit adipocyte differentiation. Protease inhibitors used in the treatment of human immunodeficiency virus infection are known to cause a lipodystrophic syndrome and central obesity, but saquinavir, indinavir, and neflinavir caused a dose-dependent inhibition of 11betaHSD1 activity in primary cultures of human omental ASC. 11betaHSD1 expression is increased in human adipose tissue by TNFalpha, interleukin-1beta, leptin, and orphan nuclear receptor peroxisome proliferator-gamma agonists, but is inhibited by IGF-I. This autocrine and/or paracrine regulation is tissue specific and explains recent clinical data and animal studies evaluating cortisol metabolism in obesity. Tissue-specific 11betaHSD1 regulation offers the potential for selective enzyme inhibition within adipose tissue as a novel therapy for visceral obesity.
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PMID:Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. 1131 64

Glucocorticoid excess frequently results in obesity, insulin resistance, glucose intolerance, and hypertension and may be the product of altered glucocorticoid hormone action. Tissue sensitivity to glucocorticoid is regulated by the expression of glucocorticoid receptor isoforms (GRalpha and GRbeta) and 11beta-hydroxysteroid dehydrogenase type I (11betaHSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed the expression of GRalpha, GRbeta, and 11betaHSD1 and their hormonal regulation in skeletal myoblasts from men (n = 14) with contrasting levels of adiposity and insulin resistance. Immunohistochemical, Northern blot, and Western blot analysis indicated abundant expression of GRalpha and 11betaHSD1 under basal conditions. The apparent K(m) and maximum velocity for the conversion of cortisone to cortisol were 440 +/- 14 nmol/L and 75 +/- 7 pmol/mg protein.h and 437 +/- 16 nmol/L and 33 +/- 6 pmol/mg protein.h (mean +/- SEM; n = 4) in the presence and absence of 20% serum. Incubation of myoblasts with increasing concentrations of glucocorticoid (50-1000 nmol/L) resulted in a dose-dependent decline in GRalpha expression and a dose-dependent increase in GRbeta expression. 11betaHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid (50-1000 nmol/L: P < 0.05). Abolition of these effects by the GR antagonist, RU38486, indicates that regulation of GRalpha, GRbeta, and 11betaHSD1 expression is mediated exclusively by the GRalpha ligand-binding variant. In contrast, 11betaHSD1 was down-regulated by insulin (20-100 mU/mL: P < 0.01) in the presence of 20% serum, whereas incubation with insulin under serum-free conditions resulted in a dose-dependent increase in 11betaHSD1 activity (P < 0.05). Incubation with insulin-like growth factor I resulted in a similar pattern of 11betaHSD1 activity. Although neither testosterone nor androstenedione (5-200 nmol/L) affected 11betaHSD1 activity, incubation of myoblasts with dehydroepiandrosterone (500 nmol/L) resulted in a decline in 11betaHSD1 activity (P < 0.05). These data suggest that glucocorticoid hormone action in skeletal muscle is determined principally by autoregulation of GRalpha, GRbeta, and 11betaHSD1 expression by the ligand-binding GRalpha isoform. Additionally, insulin and insulin-like growth factor I regulation of 11betaHSD1 may represent a novel mechanism that maintains insulin sensitivity in skeletal muscle tissue by diminishing glucocorticoid antagonism of insulin action.
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PMID:Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? 1134 42


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