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.
Molecular Metabolism Group after University of Edinburgh, Centre for Cardiovascular Sciences, Edinburgh, United Kingdom. nik.morton@ed.ac.uk
Nicholas Michael
NM
Morton
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