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Reduced Adipose Glucocorticoid Reactivation and Increased Hepatic Glucocorticoid Clearance as an Early Adaptation to High-Fat Feeding in Wistar Rats

Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, United Kingdom

Address all correspondence and requests for reprints to: Dr. Amanda J. Drake, Lecturer in Child Life and Health, Department of Child Life and Health, University of Edinburgh, 20 Sylvan Place, Edinburgh EH9 1UW, United Kingdom. E-mail: mandy.drake{at}ed.ac.uk.

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 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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 wk, HF rats showed no differences in weight but were glucose intolerant, had lower 11ß-HSD-1 activity in liver (3.8 ± 0.2 vs. 4.9 ± 0.2 pmol product/min·mg protein; P < 0.01), sc fat (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 5ß-reductase activity (0.26 ± 0.05 vs. 0.10 ± 0.007 pmol product/min·mg protein; P < 0.05). After 20 wk, HF rats were obese, hyperglycemic, and hyperinsulinemic, but differences in 11ß-HSD-1 and 5ß-reductase activities were no longer apparent. Mature male rats given HF diets for 24 or 72 h showed increased hepatic 5ß-reductase activity and a trend for decreased sc adipose 11ß-HSD-1 activity. Dietary obesity is not accompanied by the changes in 11ß-HSD-1 and 5ß-reductase expression and activity observed in genetically obese rodents. Acute exposure to HF 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.

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