Effects of Gonadectomy on Glucocorticoid Metabolism in Obese Zucker Rats

Glucocorticoids are metabolized by 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) and the A-ring reductases (5α- and 5β-reductases). Dysregulation of these enzymes has been reported in liver and adipose tissue in obese humans and animals, potentially leading to altered intracellular glucocorticoid concentrations and compensatory activation of the hypothalamic-pituitary-adrenal axis. This dysregulation of glucocorticoid metabolism in obesity is poorly understood. We hypothesized that changes in glucocorticoid metabolism in obesity are mediated by alterations in androgen action. Steroid metabolism was studied in obese and lean male Zucker rats (age 10 wk, 10 animals per group) 4 wk after gonadectomy or sham surgery. Oral glucose tolerance tests were performed, and activities and abundances of mRNAs for steroid metabolizing enzymes were quantified in liver and adipose tissue. Gonadectomy did not consistently alter weight gain, glucose intolerance, or hyperinsulinemia in obese animals. Gonadectomy increased adrenal mass (P < 0.05), suppressed 11βHSD1 activity and/or mRNA in liver and adipose, increased 5α-reductase 1 mRNA in liver (P < 0.05), and increased 5β-reductase activity only in obese animals (P < 0.05). Differences in hepatic 11βHSD1 mRNA expression and adipose activity between lean and obese animals were normalized by gonadectomy, whereas obese gonadectomized animals maintained elevated liver 5α-reductase and had an exaggerated elevation of 5β-reductase activity. We conclude that androgens tonically increase 11βHSD1 in liver and adipose tissue in male rats and contribute to the dysregulation of 11βHSD1 in obesity. By contrast, androgens tonically suppress hepatic A-ring reductases in male rats and do not contribute to dysregulation of these enzymes in obesity.