OR03-2 11-HSD1 Knockout Mice are Protected from the Adverse Metabolic Effects of Exogenous Glucocorticoid Excess

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR03-Glucocorticoids & Glucocorticoid Actions
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 11:45 AM
Room 130 (Moscone Center)
Stuart Andrew Morgan*1, Iwona Bujalska2, Laura Louise Gathercole2, Zaki K Hassan-Smith2, Paul Michael Stewart2, Jeremy W Tomlinson2 and Gareth Geoffrey Lavery2
1University of Birmingham, United Kingdom, 2University of Birmingham, Birmingham, United Kingdom
Glucocorticoids (GC), such as prednisolone, are widely prescribed for their anti-inflammatory and immunosuppressive properties. However, they have significant side-effects including insulin resistance and hepatic steatosis. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts 11-dehydrocorticosterone (11DHC) to active corticosterone (CORT) and thus amplifies local GC action. We hypothesise that enhanced local GC regeneration of exogenously administered GCs by 11β-HSD1 may contribute to the adverse side-effect profile. To test this hypothesis, 6-week old male 11β-HSD1-/- and wildtype (WT) mice were treated with CORT(100μg/mL), 11DHC(100μg/mL) or vehicle via the drinking water. After 5 weeks, animals underwent glucose tolerance testing and were sacrificed for assessment of metabolic parameters. As anticipated, 11DHC treated 11β-HSD1-/- mice were indistinguishable from vehicle treated mice. CORT and 11DHC treated WT mice displayed impaired glucose tolerance, hepatic steatosis and increased hepatic expression of the fatty acid transporter CD36. However, 11β-HSD1-/- CORT treated mice were protected from glucose intolerance, hepatic steatosis and had lower hepatic CD36 expression. In CORT treated WT adipose tissue, 11β-HSD1 and hormone sensitive lipase (HSL) expression were elevated, associated with increased circulating free fatty acid (FFA) levels. Conversely, CORT treated 11β-HSD1-/- mice were protected from elevated HSL expression and increased circulating FFAs. Finally, intramyocellular diacylglyceride (DAG) content was elevated in CORT and 11DHC treated WT mice, whereas CORT treated 11β-HSD1-/- mice were protected from increased DAG levels, a possible factor in improved glucose tolerance. Importantly, both WT and 11β-HSD1-/- CORT treated mice had a similar increased circulating CORT (500nmol/mL) compared to vehicle controls (50nmol/mL). These data demonstrate that 11β-HSD1-/- mice are protected from the adverse effects of exogenous GC excess, and suggest that local GC regeneration may contribute significantly to the adverse effect profile of therapeutic GC use. This raises the possibility of using selective 11β-HSD1 inhibitors as an adjunctive therapy to limit the side-effects of GC treatment.

Nothing to Disclose: SAM, IB, LLG, ZKH, PMS, JWT, GGL

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