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

Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.6 yr (mean +/- SD; range, 18-45). Adipose 11-HSD1 activity and mRNA levels were highly correlated (r = 0.51, P = 0.003). Adipose 11-HSD1 activity was positively related to measures of total (body mass index, percentage body fat) and central (waist circumference) adiposity (P < 0.05 for all) and fasting glucose (r = 0.43, P = 0.02), insulin (r = 0.60, P = 0.0005), and insulin resistance by the homeostasis model (r = 0.70, P < 0.0001) but did not differ between sexes or ethnic groups. Intra-adipose cortisol was positively associated with fasting insulin (r = 0.37, P = 0.04) but was not significantly correlated with 11-HSD1 mRNA or activity or with other metabolic variables. In this cross-sectional study, higher adipose 11-HSD1 activity is associated with features of the metabolic syndrome. Our data support the hypothesis that increased regeneration of cortisol in adipose tissue influences metabolic sequelae of human obesity.
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PMID:Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. 1278 82

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension. Taken together, our findings suggest that overexpression of 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11beta-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.
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PMID:Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. 1284 62

Two isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 acts predominantly as an oxo-reductase in vivo using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 is a NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tIssues, both enzymes serve to control the availability of cortisol to bind to corticosteroid receptors. 11beta-HSD2 protects the mineralocorticoid receptor from cortisol excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of 'apparent mineralocorticoid excess', in which 'Cushing's disease of the kidney' results in cortisol-mediated mineralocorticoid excess. Inhibition of 11beta-HSD2 explains the mineralocorticoid excess state seen following liquorice ingestion and more subtle defects in enzyme expression might be involved in the pathogenesis of 'essential' hypertension. 11beta-HSD1 by generating cortisol in an autocrine fashion facilitates glucocorticoid receptor-mediated action in key peripheral tIssues including liver, adipose tissue, bone and the eye. 'Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of central obesity and raises the exciting possibility of selective 11beta-HSD1 inhibition as a novel therapy for patients with the metabolic syndrome. 'Pre-receptor' metabolism of cortisol via 11beta-HSD isozymes is an important facet of corticosteroid hormone action. Aberrant expression of these isozymes is involved in the pathogenesis of diverse human diseases including hypertension, insulin resistance and obesity. Modulation of enzyme activity may offer a future therapeutic approach to treating these diseases whilst circumventing the endocrine consequences of glucocorticoid excess or deficiency.
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PMID:Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. 1294 16

Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11beta-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11beta-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11beta-HSD1 activity.
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PMID:11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes. 1465 20

Androgen excess in women with polycystic ovary syndrome (PCOS) may be ovarian and/or adrenal in origin, and one proposed contributing mechanism is altered cortisol metabolism. Increased peripheral metabolism of cortisol may occur by enhanced inactivation of cortisol by 5alpha-reductase (5alpha-R) or impaired reactivation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) resulting in decreased negative feedback suppression of ACTH secretion maintaining normal plasma cortisol concentrations at the expense of androgen excess. We have tested whether any enzyme dysregulation was related to circulating insulin or androgen concentrations in women with PCOS and have sought to clarify their relationship with obesity. First, to avoid obesity-related effects on cortisol metabolism, 18 lean women with PCOS were compared with 19 lean controls who were closely matched for body mass index (BMI). Second, the impact of obesity was studied in a cross-section of 42 PCOS women of a broad range of BMI. We measured 24-h urinary excretion of steroid metabolites by gas chromatography/mass spectrometry and fasting metabolic and hormone profiles. Urinary excretion of androgens [androsterone (P = 0.003), etiocholanolone (P = 0.02), and C19 steroid sulfates (P = 0.009)], cortisone metabolites [tetrahydrocortisone (THE) (P = 0.02), alpha-cortolone (P < 0.001), beta-cortol + beta-cortolone (P < 0.001), cortolones (P < 0.001), and E metabolites (P < 0.001)], and TCM (P = 0.002) were raised in lean PCOS subjects when compared with controls. A significantly higher 5alpha-tetrahydrocortisol (5alpha-THF)/5beta-THF ratio (P = 0.04) and a significantly lower alpha-THF + THF + alpha-cortol/THE + cortolones ratio (P = 0.01) were found in lean PCOS women compared with lean controls, indicating both enhanced 5alpha-R and reduced 11beta-HSD1 activities. A decreased THE/cortolones ratio (P = 0.03) was also found in lean PCOS women compared with lean controls, indicating increased 20 alpha/beta-HSD activity. In the group of 42 PCOS subjects, measures of 5alpha/5beta reduction were positively correlated with the homeostasis model insulin resistance index (HOMA-R): alpha-THF/THF and HOMA-R (r = 0.34; P = 0.03), androsterone/etiocholanolone and HOMA-R (r = 0.32; P = 0.04), and total 5alpha /total 5beta and HOMA-R (r = 0.37; P = 0.02). A positive correlation was also found between measures of 5alpha-R and BMI (r = 0.37; P = 0.02). No correlation was found between measures of 11beta-HSD1 activity and indices of insulin sensitivity or BMI. We have demonstrated that there is an increased production rate of cortisol and androgens as measured in vivo in lean PCOS women. Insulin seems to enhance 5alpha reduction of steroids in PCOS but was not associated with the elevated cortisol production rate. The changes in 5alpha-R, 11beta-HSD1, and 20alpha/beta-HSD enzyme activities observed in PCOS may contribute to the increased production rates of cortisol and androgens, supporting the concept of a widespread dysregulation of steroid metabolism. This dysregulation does not seem to be the primary cause of PCOS because no correlation was found between serum androgen levels or urinary excretion of androgens with measurements of either 5alpha-R or 11beta-HSD1 activities.
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PMID:Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal steroid production rates. 1467 Nov 89

Several factors including genetic and environmental play a role in the development of obesity and the metabolic syndrome. The transgenic mouse overexpressing 11beta-hydroxysteroid dehydrogenase (11beta-HSD) develops visceral obesity. However, it remains unclear how a ubiquitously expressed 11beta-HSD1 enzyme affects adipose tissue so much that it would lead to obesity. In this commentary we explore the possibility that increased intracellular availability of reduced co-factor, NADPH, could exacerbate the enzymatic activity.
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PMID:Cortisol metabolism and visceral obesity: role of 11beta-hydroxysteroid dehydrogenase type I enzyme and reduced co-factor NADPH. 1468 70

Obesity is closely associated with the Metabolic Syndrome, which includes insulin resistance, glucose intolerance, dyslipidemia and hypertension. The best predictor of these morbidities is not the total body fat mass but the quantity of visceral (e.g. omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Indeed, patients with Cushing-s syndrome (a rare disease characterized by systemic glucocorticoid excess originating from the adrenal or pituitary tumors) or receiving glucocorticoid therapy develop reversible visceral fat obesity. The role of glucocorticoids in prevalent forms of human obesity, however, has remained obscure, because circulating glucocorticoid concentrations are not elevated in the majority of obese subjects. Glucocorticoid action on target tissue depends not only on circulating levels but also on intracellular concentration. Locally enhanced action of gluccorticoids in adipose tissue and skeletal muscle has been demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. Furthermore, fat-specific 11beta-HSD1 transgenic mice, those have increased enzyme activity to a similar extent seen in obese humans, develop visceral obesity with insulin and leptin resistance, dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARgamma agonists and LXRalpha agonists significantly reduce 11beta-HSD1 mRNA and enzyme activity, suggesting that suppression of 11beta-HSD1 in adipose tissue may be one of the mechanisms by which these drugs exert beneficial metabolic effects. Recently reported selective inhibitors of 11beta-HSD1 can ameliorate severe hyperglycemia in the genetically diabetic obese mice. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome.
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PMID:Tissue-specific glucocorticoid reactivating enzyme, 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1)--a promising drug target for the treatment of metabolic syndrome. 1468 56

The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action. 11beta-HSD1 is elevated in adipose tissue in obese humans and rodents, suggesting that adipose tissue glucocorticoid excess may explain the conundrum. Indeed, transgenic mice overexpressing 11beta-HSD1 in adipose tissue faithfully replicate the metabolic syndrome. Conversely, 11beta-HSD1(-/-) mice resist the metabolic consequences of stress and high-fat feeding via insulin sensitisation and other advantageous effects in the liver and adipose tissue. Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome.
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PMID:Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. 1474 10

In obese humans and rodents there is increased expression of the key glucocorticoid (GC) regenerating enzyme, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), in adipose tissue. This increased expression appears to be of pathogenic importance because transgenic mice overexpressing 11beta-HSD1 selectively in adipose tissue exhibit a full metabolic syndrome with visceral obesity, dyslipidemia, insulin-resistant diabetes, and hypertension. In this model, while systemic plasma GC levels are unaltered, GC delivery to the liver via the portal vein is increased. 11beta-HSD1 is most highly expressed in liver where inhibition or deficiency of its activity improves glucose and lipid homeostasis. To determine the potential contribution of elevated intrahepatic GCs alone toward development of insulin-resistant syndromes we generated transgenic mice expressing increased 11beta-HSD1 activity selectively in the liver under transcriptional control of hepatic regulatory sequences derived from the human apoE gene (apoE-HSD1). Transgenic lines with 2- and 5-fold-elevated 11beta-HSD1 activity exhibited mild insulin resistance without altered fat depot mass. ApoE-HSD1 transgenic mice exhibited fatty liver and dyslipidemia with increased hepatic lipid synthesis/flux associated with elevated hepatic LXRalpha and PPARalpha mRNA levels as well as impaired hepatic lipid clearance. Further, apoE-HSD1 transgenic mice have a marked, transgene-dose-associated hypertension paralleled by incrementally increased liver angiotensinogen expression. These data suggest that elevated hepatic expression of 11beta-HSD1 may relate to the pathogenesis of specific fatty liver, insulin-resistant, and hypertensive syndromes without obesity in humans as may occur in, for example, myotonic dystrophy, and possibly, the metabolically obese, normal-weight individual.
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PMID:Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. 1511 95

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P <.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P <.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P <.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P <.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors.
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PMID:Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats. 1513 64


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