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.
Morton
Nicholas Michael
NM
Molecular Metabolism Group after University of Edinburgh, Centre for Cardiovascular Sciences, Edinburgh, United Kingdom. nik.morton@ed.ac.uk
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000818:Animals; D003480:Cushing Syndrome / Q000378:metabolism / Q000503:physiopathology; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D014018:Tissue Distribution
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone