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)

Dysfunction of the hypothalamic-pituitary-adrenal axis might contribute to metabolic disturbances frequently encountered in myotonic dystrophy. We hypothesized that abnormal adrenocortical sensitivity to ACTH and/or glucocorticoid metabolism could be important in myotonic dystrophy. We assessed diurnal rhythmicity of saliva cortisol, adrenocortical reactivity by a low-dose (1 microg) Synacthen test, and glucocorticoid metabolism in blood and urine in 42 myotonic dystrophy patients (22 males) and 50 controls (27 males). CTG triplet repeat expansions were quantified by Southern blot. Diurnal rhythmicity of saliva cortisol was flattened in both men and women with myotonic dystrophy, with significantly increased afternoon/evening levels (P < 0.013). The cortisol response to ACTH was associated with increased (CTG)(n) expansions in myotonic dystrophy men and women (P < 0.01). Male myotonic dystrophy patients also had increased activation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1. Both men and women with myotonic dystrophy had an increased 5alpha/5beta-reductase ratio (P < 0.05 and P < 0.01, respectively). Cortisol metabolites were related to the genetic defect in myotonic dystrophy men (P < 0.05), whereas ratios reflecting 11beta-hydroxysteroid dehydrogenase type 1 activity in myotonic dystrophy women were positively associated with obesity (P < 0.05). Increased 11beta-hydroxysteroid dehydrogenase type 1 activity and adrenocortical reactivity to ACTH are related to the genetic defect in myotonic dystrophy men, whereas abnormal glucocorticoid metabolism is associated with alterations in body composition in female myotonic dystrophy patients. These disturbances may explain altered circulating cortisol levels and contribute to features of the metabolic syndrome in myotonic dystrophy.
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PMID:Glucocorticoid metabolism and adrenocortical reactivity to ACTH in myotonic dystrophy. 1154 62

In liver and adipose tissue, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates glucocorticoids from inactive 11-keto metabolites. Pharmacological inhibition or transgenic disruption of 11beta-HSD1 attenuates glucocorticoid action and increases insulin sensitivity. Increased adipose 11beta-HSD1 may also contribute to the metabolic complications of obesity. Here, we examine the effects of inhibition of 11beta-HSDs with carbenoxolone in obese insulin-resistant Zucker rats, a strain in which tissue-specific dysregulation of 11beta-HSD1 (increased in adipose, decreased in liver) mirrors changes in human obesity. Six-week-old male rats were treated orally with carbenoxolone (50 mg/kg/day) or water (1 ml/kg/day) for 3 weeks. Carbenoxolone inhibited 11beta-HSD1 activity in liver (25 +/- 3 versus 52 +/- 2% conversion in lean; 18 +/- 3 versus 35 +/- 3% in obese; p < 0.01) but not in adipose tissue or skeletal muscle. Carbenoxolone had no effect on weight gain or food intake, did not affect plasma glucose during an oral glucose tolerance test, and increased the plasma insulin response to glucose. However, high-density lipoprotein cholesterol was increased by carbenoxolone in obese animals (1.52 +/- 0.24 versus 1.21 +/- 0.26 mM; p < 0.03). Carbenoxolone did not inhibit hepatic inactivation of glucocorticoid by 5beta-reductase and had no significant effect on plasma corticosterone levels. In conclusion, carbenoxolone provides a model for liver-specific inhibition of 11beta-HSD1, which results in improved lipid profile, in Zucker obese rats. Failure to inhibit 11beta-HSD1 in adipose tissue and/or skeletal muscle may explain the lack of effect on glucose tolerance and obesity. Inhibition of adipose 11beta-HSD1 is probably necessary to gain the maximum benefit of an 11beta-HSD1 inhibitor.
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PMID:Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats. 1264 65

In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess. Increased inactivation of cortisol by 5alpha- and 5beta-reductases in the liver may drive compensatory activation of the hypothalamic-pituitary-adrenal axis, hence increasing adrenal androgens and 'android' central obesity. This study aimed to examine relationships between these enzymes and detailed measurements of body fat distribution. Twenty-five healthy men (age, 22-57 yr; body mass index, 20.6-35.6 kg/m(2)) were recruited from occupational health services. Body composition was assessed by anthropometric measurements, bioimpedance, and cross-sectional abdominal magnetic resonance imaging scans. Liver fat content was assessed by magnetic resonance imaging spectroscopy. Insulin sensitivity was measured in a euglycemic hyperinsulinemic clamp. Cortisol metabolites were measured in a 24-h urine sample by gas chromatography-mass spectrometry. In vivo hepatic 11HSD1 activity was measured by generation of plasma cortisol after an oral dose of cortisone. In vitro 11HSD1 activity and mRNA were measured in 18 subjects who consented to provide abdominal sc adipose biopsies. Indices of obesity (body mass index, whole-body percentage fat, waist/hip ratio) were associated with higher urinary excretion of 5alpha- and 5beta-reduced cortisol metabolites (for percentage fat, P < 0.05 and P < 0.01, respectively) and increased adipose 11HSD1 activity (P < 0.05). Liver fat accumulation was associated with a selective increase in urinary excretion of 5beta-reduced cortisol and cortisone metabolites (P < 0.01) and a lower ratio of cortisol/cortisone metabolites in urine (P < 0.001) but no difference in in vivo cortisone-to-cortisol conversion or in vitro adipose 11HSD1. Higher excretion of 5beta-reduced cortisol metabolites was independently associated with insulin resistance and hypertriglyceridemia. Lower conversion of cortisone to cortisol was associated with lower fasting plasma cortisol (P < 0.01). However, visceral adipose fat mass was not associated with indices of cortisol metabolism; indeed, after adjusting for the effects of whole-body and liver fat, increased visceral fat was associated with lower cortisol metabolite excretion. We conclude that alterations in 11HSD1 and hepatic 5alpha-reductase activity are associated with generalized, rather than central, obesity in humans. Activation of 5beta-reductase in men with fat accumulation in the liver may confound the interpretation of cortisol metabolite excretion when liver fat content is unknown, and may contribute to altered bile acid and cholesterol metabolism in nonalcoholic steatohepatitis.
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PMID:Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. 1455 75

Altered peripheral glucocorticoid metabolism may be important in the pathogenesis of obesity in humans and animal models. Genetically obese Zucker rats, Lep/ob mice, and obese humans exhibit increased regeneration of active glucocorticoids selectively in adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) and increased glucocorticoid clearance by hepatic A-ring reductases. We have examined whether dietary obesity in rats induces the same changes in glucocorticoid metabolism. Male Wistar rats were weaned onto high-fat (HF; 45% kcal from fat) or control (10% fat) diets. After 3 wk, HF rats showed no differences in weight but were glucose intolerant, had lower 11beta-HSD-1 activity in liver (3.8 +/- 0.2 vs. 4.9 +/- 0.2 pmol product/min.mg protein; P <0.01), sc fat (0.03 +/- 0.01 vs. 0.09 +/- 0.01 pmol product/min.mg protein; P <0.01), and omental fat (0.02 +/- 0.001 vs. 0.03 +/- 0.003 pmol/ product/min.mg protein; P <0.05) and higher hepatic 5beta-reductase activity (0.26 +/- 0.05 vs. 0.10 +/- 0.007 pmol product/min.mg protein; P <0.05). After 20 wk, HF rats were obese, hyperglycemic, and hyperinsulinemic, but differences in 11beta-HSD-1 and 5beta-reductase activities were no longer apparent. Mature male rats given HF diets for 24 or 72 h showed increased hepatic 5beta-reductase activity and a trend for decreased sc adipose 11beta-HSD-1 activity. Dietary obesity is not accompanied by the changes in 11beta-HSD-1 and 5beta-reductase expression and activity observed in genetically obese rodents. Acute exposure to HF diet alters glucocorticoid metabolism, predicting lower hepatic and adipose intracellular glucocorticoid concentrations, which may be a key mechanism protecting against the metabolic complications of obesity.
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PMID:Reduced adipose glucocorticoid reactivation and increased hepatic glucocorticoid clearance as an early adaptation to high-fat feeding in Wistar rats. 1555 May 7

Glucocorticoids are metabolized by 11beta-hydroxysteroid dehydrogenase 1 (11betaHSD1) and the A-ring reductases (5alpha- and 5beta-reductases). Dysregulation of these enzymes has been reported in liver and adipose tissue in obese humans and animals, potentially leading to altered intracellular glucocorticoid concentrations and compensatory activation of the hypothalamic-pituitary-adrenal axis. This dysregulation of glucocorticoid metabolism in obesity is poorly understood. We hypothesized that changes in glucocorticoid metabolism in obesity are mediated by alterations in androgen action. Steroid metabolism was studied in obese and lean male Zucker rats (age 10 wk, 10 animals per group) 4 wk after gonadectomy or sham surgery. Oral glucose tolerance tests were performed, and activities and abundances of mRNAs for steroid metabolizing enzymes were quantified in liver and adipose tissue. Gonadectomy did not consistently alter weight gain, glucose intolerance, or hyperinsulinemia in obese animals. Gonadectomy increased adrenal mass (P < 0.05), suppressed 11betaHSD1 activity and/or mRNA in liver and adipose, increased 5alpha-reductase 1 mRNA in liver (P < 0.05), and increased 5beta-reductase activity only in obese animals (P < 0.05). Differences in hepatic 11betaHSD1 mRNA expression and adipose activity between lean and obese animals were normalized by gonadectomy, whereas obese gonadectomized animals maintained elevated liver 5alpha-reductase and had an exaggerated elevation of 5beta-reductase activity. We conclude that androgens tonically increase 11betaHSD1 in liver and adipose tissue in male rats and contribute to the dysregulation of 11betaHSD1 in obesity. By contrast, androgens tonically suppress hepatic A-ring reductases in male rats and do not contribute to dysregulation of these enzymes in obesity.
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PMID:Effects of gonadectomy on glucocorticoid metabolism in obese Zucker rats. 1762 1

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