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 i n obese men suggest enhanced inactivation of cortisol by 5 alpha-reductase and altered reactivation of cortisone to cortisol by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1). These changes in glucocorticoid metab olism may influence corticosteroid receptor activation and feedback regulat ion of the hypothalamic-pituitary-adrenal axis (HPA). We have compared cort icosterone metabolism in vivo and in vitro in male obese and lean Zucker ra ts, aged 9 weeks (n = 8/group). Steroids were measured in 72-h urine and 09 00 h trunk blood samples. 5 alpha-Reductase type 1 and 11 beta HSD activiti es were assessed in dissected tissues. Obese animals were hypercorticostero nemic and excreted more total corticosterone metabolites (2264 +/- 623 us. 388 +/- 144 ng/72 h; P = 0.003), with a greater proportion being 5 alpha-re duced or 11-oxidized. 11-Dehydrocorticosterone was also elevated in plasma (73 +/- 9 us. 18 +/- 2 nM; P = 0.001) and urine (408 +/- 111 us. <28 ng/72 h; P = 0.01). In liver of obese rats, 5 alpha-reductase type 1 activity was greater (20.6 +/- 2.7% vs. 14.1 +/- 1.5%; P < 0.04), but 11 beta HSD1 acti vity (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, 11 beta HSD 1 activity was no t 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 11 beta HSD2 activity was h igher in kidney (16.7 +/- 0.6% us. 11.3 +/- 1.5%; P = 0.01). We conclude that greater inactivation of glucocorticoids by 5 alpha-reducta se in liver and 11 beta HSD2 in kidney combined with impaired reactivation of glucocorticoids by 11 beta HSD1 in liver may increase the MCR of glucoco rticoids and decrease local glucocorticoid concentrations at these sites. B y contrast, enhanced 11 beta HSD1 in omental adipose tissue may increase lo cal glucocorticoid receptor activation and promote obesity.