Understanding the Role of Glucocorticoids in Obesity: Tissue-Specific Alterations of Corticosterone Metabolism in Obese Zucker Rats

The role of glucocorticoids in obesity is poorly understood. Observations in obese men suggest enhanced inactivation of cortisol by 5α-reductase and altered reactivation of cortisone to cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). These changes in glucocorticoid metabolism may influence corticosteroid receptor activation and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA). We have compared corticosterone metabolism in vivo and in vitro in male obese and lean Zucker rats, aged 9 weeks (n= 8/group). Steroids were measured in 72-h urine and 0900 h trunk blood samples. 5α-Reductase type 1 and 11βHSD activities were assessed in dissected tissues. Obese animals were hypercorticosteronemic and excreted more total corticosterone metabolites (2264 ± 623 vs. 388 ± 144 ng/72 h; P = 0.003), with a greater proportion being 5α-reduced or 11-oxidized. 11-Dehydrocorticosterone was also elevated in plasma (73 ± 9 vs. 18 ± 2 nm; P = 0.001) and urine (408 ± 111 vs. <28 ng/72 h; P = 0.01). In liver of obese rats, 5α-reductase type 1 activity was greater (20.6 ± 2.7% vs. 14.1 ± 1.5%; P < 0.04), but 11βHSD1 activity (maximum velocity, 3.43 ± 0.56 vs. 6.57 ± 1.13 nmol/min/mg protein; P = 0.01) and messenger RNA levels (0.56 ± 0.08 vs. 1.03 ± 0.15; P = 0.02) were lower. In contrast, in obese rats, 11βHSD1 activity was not different in skeletal muscle and sc fat and was higher in omental fat (36.4 ± 6.2 vs. 19.2 ± 6.6; P = 0.01), whereas 11βHSD2 activity was higher in kidney (16.7 ± 0.6% vs. 11.3 ± 1.5%; P = 0.01). We conclude that greater inactivation of glucocorticoids by 5α-reductase in liver and 11βHSD2 in kidney combined with impaired reactivation of glucocorticoids by 11βHSD1 in liver may increase the MCR of glucocorticoids and decrease local glucocorticoid concentrations at these sites. By contrast, enhanced 11βHSD1 in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity.