Obesity is associated with hypothalamic-pituitary-adrenal (HPA) axis activation. In obese humans and leptin-resistant obese Zucker rats, we have reported increased excretion of A-ring reduced glucocorticoid metabolites. We have now investigated regulation of hepatic A-ring reductases in the obese Zucker rat.
Lean and obese Zucker rats (9wks) were studied either: 3-weeks after adrenalectomy (ADX) or sham surgery; or after 3-weeks treatment with metformin (MET; 43mg/kg/d), rosiglitazone (ROS; 1mg/kg/d) or water (VEH; 1ml/kg/d): n=8/group. Insulin sensitivity was increased in obese animals with MET or ROS. Hepatic mRNA was quantified by Northern blot as arbitrary units (AU), and 5beta-reduction of tritiated corticosterone was measured in liver cytosol as percent conversion (%).
Both mRNA (1.4+/-0.2 v 0.83+/-0.35 AU; p=0.01) and activity (10.7+/-0.6 v 7.7+/-0.3%; p=0.001) of 5beta-reductase were higher in obese animals. mRNA for hepatic 5alpha-reductase type 1 was also higher in obese animals (1.2+/-0.26 v 0.48+/-0.05 AU; p=0.02). Neither ADX nor insulin-sensitising drugs altered hepatic A-ring reductases in lean animals. By contrast, in obese animals ADX exacerbated elevated 5beta-reductase activity (19.7+/-1.4 obese-ADX v 14.8+/-0.7% obese-sham; p=0.002) but reduced 5alpha-reductase type 1 expression (105+/-13 obese-ADX v 340+/-59 AU obese-sham; p=0.003). Insulin sensitisation in obese animals was associated with a small decrease in 5beta-reductase activity (9.4+/-0.4 obese-MET v 10.7+/-0.6% obese-VEH; p=0.04) and normalised 5alpha-reductase type 1 expression (0.43+/-0.11 obese-MET and 0.35+/-0.08 obese-ROS v 1.14+/-0.26 AU obese-VEH; p<0.001).
So, increased excretion of urinary A-ring reduced corticosterone metabolites in obese Zucker rats can be explained by increased expression and activity of hepatic A-ring reductases. We have now shown that glucocorticoids and insulin contribute to the regulation of these enzymes. Furthermore, normalisation of increased hepatic A-ring reduction in obesity is associated with reversal of adrenal hypertrophy, demonstrating a role for peripheral metabolic clearance of glucocorticoids in regulating HPA axis activation.