11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess
Stuart A Morgan, Emma L McCabe, Laura L Gathercole, Zaki K Hassan-Smith, Dean P Larner, Iwona J Bujalska, Paul M Stewart, Jeremy W Tomlinson, Gareth G Lavery, Stuart A Morgan, Emma L McCabe, Laura L Gathercole, Zaki K Hassan-Smith, Dean P Larner, Iwona J Bujalska, Paul M Stewart, Jeremy W Tomlinson, Gareth G Lavery
Abstract
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.
Keywords: HSD11b1; cortisol; endocrinology; hypercortisolemia; steroids.
Conflict of interest statement
The authors declare no conflict of interest.
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Source: PubMed