Increased A-ring reduction of glucocorticoids in obese Zucker rats: Effects of insulin sensitization

Objective: Obesity is associated with altered glucocorticoid metabolism, which may impact on hypothalamic-pituitaryadrenal axis activity. Here we characterize hepatic 5α- and 5β-reductase in obese rats and their responses to insulin sensitization. Research Methods and Procedures: Hepatic A-ring reductase protein and mRNA were assessed in lean and obese Zucker rats after insulin sensitization with metformin or rosiglitazone (n = 7 to 8/group). Results: Hepatic 5α-reductase 1 and 5β-reductase mRNA and protein (p < 0.01) were increased in obese rats. Insulin sensitization ameliorated increased 5α-reductase 1 mRNA in obese rats (p < 0.01) and partially reversed increased 5β-reductase activity. Discussion: Hepatic clearance of glucocorticoids by 5αand 5β-reductase is increased in obese Zucker rats, and this increase in clearance is attenuated by insulin sensitization. This increased hepatic clearance may underpin compensatory activation of the hypothalamic-pituitary-adrenal axis in obesity.