Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease.

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.