Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.
Central obesity is associated with type 2 diabetes mellitus, hypertension and dyslipidaemia. This cluster of risk factors is known as the metabolic syndrome, and also occurs in people with primary glucocorticoid excess (Cushing's syndrome). Exogenous glucocorticoid use also increases the risk of cardiovascular disease. Circulating glucocorticoid concentrations are tightly controlled by the hypothalamic-pituitary-adrenal axis, however tissue glucocorticoid levels are also enhanced by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Transgenic overexpression of 11beta-HSD1 in either adipose tissue or the liver in mice causes components of the metabolic syndrome, while transgenic deletion of 11beta-HSD1 prevents adverse metabolic complications of obesity. Although plasma glucocorticoid levels are not elevated in obesity, dysregulation of 11beta-HSD1 is observed with decreased activity in the liver and increased activity in adipose tissue. 11beta-HSD1 is highly regulated, and dietary composition may be a powerful determinant of activity. Polymorphisms in the 11beta-HSD1 gene are also associated with components of the metabolic syndrome. Inhibition of this enzyme appears to be an attractive option to treat metabolic disease. Selective 11beta-HSD1 inhibitors in rodents cause weight loss, improve insulin sensitivity and delay progression of cardiovascular disease. Trials in humans though will be the ultimate test to determine if inhibition of 11beta-HSD1 offers a new tool in the treatment of metabolic disease.
Stimson
R H
RH
Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK. roland.stimson@ed.ac.uk
Walker
B R
BR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000273:Adipose Tissue / Q000201:enzymology; D000328:Adult; D000818:Animals; D002229:Carbenoxolone / Q000627:therapeutic use; D003480:Cushing Syndrome / Q000503:physiopathology; D004032:Diet; D005938:Glucocorticoids / Q000502:physiology*; D006801:Humans; D017588:Hyperandrogenism / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008099:Liver / Q000201:enzymology; D008297:Male; D024821:Metabolic Syndrome / Q000201:enzymology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D009928:Organ Specificity; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D051381:Rats
D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D002229:Carbenoxolone