Altered peripheral glucocorticoid metabolism may be important in the pathogenesis of obesity in humans and animal models. Genetically obese Zucker rats, lep/ob mice and obese humans exhibit increased regeneration of active glucocorticoids selectively in adipose tissue by 11-hydroxysteroid dehydrogenase type 1 (11-HSD-1) and increased glucocorticoid clearance by hepatic A-ring reductases. We have examined whether dietary obesity in rats induces the same changes in glucocorticoid metabolism.

Male Wistar rats were weaned onto high-fat (HF; 45% kcal from fat) or control (10% fat) diets. After 3 weeks, HF rats showed no differences in weight, but were glucose intolerant, had lower 11-HSD-1 activity in liver (3.8 ± 0.2 vs. 4.9 ± 0.2 pmol product/min/mg protein, P < 0.01), subcutaneous (0.03 ± 0.01 vs. 0.09 ± 0.01 pmol product/min/mg protein, P < 0.01) and omental fat (0.02 ± 0.001 vs. 0.03 ± 0.003 pmol/ product/min/mg protein, P < 0.05), and higher hepatic 5-reductase activity (0.26 ± 0.05 vs. 0.10 ± 0.007 pmol product/min/mg protein, P < 0.05). After 20 weeks, HF rats were obese, hyperglycaemic and hyperinsulinaemic but differences in 11-HSD-1 and 5-reductase activities were no longer apparent. Mature male rats given HF diets for 24 or 72 h showed increased hepatic 5-reductase activity and a trend for decreased subcutaneous adipose 11-HSD-1 activity.

Dietary obesity is not accompanied by the changes in 11-HSD-1 and 5-reductase expression and activity observed in genetically obese rodents. Acute exposure to high-fat diet alters glucocorticoid metabolism, predicting lower hepatic and adipose intracellular glucocorticoid concentrations which may be a key mechanism protecting against the metabolic complications of obesity.