Endocrine Abstracts

5beta-Reductase is a key glucocorticoid metabolising enzyme. In humans, urinary steroid metabolite profiles suggest an inverse relationship between 5beta-reductase and 11beta-hydroxysteroid dehydrogenase (11HSD1) in obesity and congenital deficiency of 11HSDs. Indeed in the obese Zucker rat hepatic 11HSD1 is decreased and 5beta-reductase increased. Here we use animal models with well characterised alterations in 11HSD1 to explore the link between these enzymes.
11HSD1 was manipulated by pharmacological inhibition in obese Zucker rats (carbenoxolone; 50mg/kg/d for 3wks; n=8/group), and by transgenic disruption in 11HSD1 knock-out mice (n=6/group). 5beta-Reductase activity was measured by conversion of corticosterone to 5beta-tetrahydrocorticosterone. Inhibition of hepatic 11HSD1 with carbenoxolone increased 5beta-reductase in obese Zucker rats (16.1 plus/minus 0.8 vs 12.5 plus/minus 0.3%; p<0.001) compared with vehicle treated controls (water; 1ml/kg/d). By contrast, 11HSD1 knock-out mice had decreased hepatic 5beta-reductase activity (5.1 plus/minus 0.9 vs 31.6 plus/minus 2.85%; p<0.001) compared with wild-types. This suggests increased 5beta-reductase in obesity is not determined simply by decreased hepatic 11HSD1.
Since, in contrast with obese Zucker rats, 11HSD1 knock-out mice are resistant to obesity and have improved glucose tolerance, we considered the impact of the metabolic phenotype on regulation of 5beta-reductase. High-fat feeding of Wistar rats (45%kcal from fat for 3wks) induced glucose intolerance and increased 5beta-reductase activity (25.3 plus/minus 4.9 vs 9.7 plus/minus 0.6%; p<0.01; n=8/group) compared with control fed animals (10%kcal from fat). Furthermore, metformin treatment of obese Zucker rats (43mg/kg/d for 3wks) improved glucose tolerance and decreased hepatic 5beta-reductase activity (9.4 plus/minus 0.5 vs 10.7 plus/minus 0.6%; p<0.05; n=8/group) compared with vehicle treated animals (water; 1ml/kg/d).
In summary, these results provide evidence for dissociation between 11HSD1 deficiency and 5beta-reductase activation, and suggest that changes in 5beta-reductase activity may be due to altered metabolic phenotype, e.g. glucose intolerance, rather than changes in 11HSD1 per se.