Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity.
Excessive glucocorticoid exposure (Cushing's syndrome) results in increased adiposity associated with dysmetabolic features (including insulin resistance, hyperlipidaemia, and hypertension). Circulating cortisol levels are not elevated in idiopathic obesity, although cortisol production and clearance are increased. However, tissue glucocorticoid exposure may be altered independently of circulating levels by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme which generates active glucocorticoid within tissues, including in adipose tissue. Transgenic overexpression of 11HSD1 in mice causes obesity. In human obesity, 11HSD1 is altered in a tissue-specific manner with reduced levels in liver but elevated levels in adipose, which may lead to glucocorticoid receptor activation and contribute to the metabolic phenotype. The reasons for altered 11HSD1 in obesity are not fully understood. Although some polymorphisms have been demonstrated in intronic and upstream regions of the HSD11B1 gene, the functional significance of these is not clear. In addition, there is mounting evidence that 11HSD1 may be dysregulated secondarily to factors that are altered in obesity, including substrates for metabolism, hormones, and inflammatory mediators. 11HSD1 is a potential therapeutic target for the treatment of the metabolic syndrome. 11HSD1 knockout mice are protected from diet-induced obesity and associated metabolic dysfunction. Although many specific inhibitors of 11HSD1 have now been developed, and published data support their efficacy in the liver to reduce glucose production, their efficacy in enhancing insulin sensitivity in adipose tissue remains uncertain. The therapeutic potential of 11HSD1 in human obesity therefore remains highly promising but as yet unproven.
Wake
Deborah J
DJ
University of Edinburgh, Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh EH16 4TJ.
Walker
Brian R
BR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D000273:Adipose Tissue / Q000201:enzymology / Q000502:physiology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D011110:Polymorphism, Genetic / Q000502:physiology
D019440:Anti-Obesity Agents; D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone