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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.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





E2482 - E2491


HSD11b1, cortisol, endocrinology, hypercortisolemia, steroids, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Adipose Tissue, Animals, Anti-Inflammatory Agents, Blood Pressure, Cushing Syndrome, Disease Models, Animal, Fatty Acids, Nonesterified, Gene Expression Regulation, Glucocorticoids, Glucose Intolerance, Glucose Tolerance Test, Hydrocortisone, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Regeneration, Triglycerides