Journal Article

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

Emma L. McCabe, Iwona J. Bujalska, Paul M. Stewart, Dean P. Larner, Jeremy W. Tomlinson, Gareth G. Lavery, Stuart A. Morgan, Laura L. Gathercole, Zaki K. Hassan-Smith

2014

Overview

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics / 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism / adipose tissue / Adipose Tissue - metabolism / adiposity / Animals / Anti-Inflammatory Agents - chemistry / atrophy / Biological Sciences / Blood Pressure / Cushing syndrome / Cushing Syndrome - blood / Cushing Syndrome - genetics / Disease Models, Animal / fatty acids / Fatty Acids, Nonesterified - blood / fatty liver / Gene Expression Regulation / Glucocorticoids - blood / glucose / Glucose Intolerance / Glucose Tolerance Test / Hydrocortisone - blood / hyperinsulinemia / hypertension / Liver - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / muscular diseases / phenotype / PNAS Plus / Regeneration - drug effects / tissue repair / Triglycerides - blood