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

Journal article

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.

Authors: Morgan, SA; McCabe, E; Gathercole, L; Hassan-Smith, Z; Larner, D

• Publication status: Published
• Publisher: National Academy of Sciences
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 111
• Issue: 24
• Pages: E2482-E2491
• Publication date: 2014-06-01
• DOI: 10.1073/pnas.1323681111
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Anti-Inflammatory Agents; Liver; Male; Fatty Acids, Nonesterified; Blood Pressure; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Cushing Syndrome; Glucose Tolerance Test; Mice, Knockout; Adipose Tissue; Hydrocortisone; Regeneration; Mice; Disease Models, Animal; Gene Expression Regulation; Triglycerides; Mice, Inbred C57BL; Glucose Intolerance; Glucocorticoids; Animals