Endocrine Abstracts (2004) 7 OC36

Tissue-specific alterations of glucocorticoid metabolism in ob/ob mice

DEW Livingstone, SL Packer, RC Kerr, NM Morton, BR Walker & R Andrew

School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, UK.

Glucocorticoid metabolism is altered in a tissue-specific manner in obesity. Increased reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1) amplifies glucocorticoid action in abdominal fat, whereas increased metabolism of glucocorticoids by hepatic A-ring reductases may contribute to activation of the hypothalamic-pituitary-adrenal axis. These changes have been characterised in leptin-resistant obese Zucker rats and obese humans. Here we investigate glucocorticoid metabolism in ob/ob obese mice, a leptin-deficient model of obesity.

Obese ob/ob mice and lean litter mates were used at 10wks (n=12). 11HSD1 activity was assessed in vitro in tissue preparations as percentage conversion of corticosterone to 11-dehydrocorticosterone, and 5beta-reductase activity as conversion of corticosterone to 5beta-tetrahydrocorticosterone. mRNA for 11HSD1 and 5beta-reductase were measured by Northern blot, relative to U1 levels. Data are mean plus/minus SEM.

In obese mice, liver 11HSD1 activity (55.5 plus/minus 2.8 vs 71.0 plus/minus 2.1%; p<0.01) and mRNA (0.75 plus/minus 0.10 vs 1.15 plus/minus 0.10 (11HSD1/U1); p=0.01) were decreased as reported previously (Liu et al (2003), Diabetes; 52; 1409). By contrast, hepatic 5beta-reductase activity (3.55 plus/minus 0.30 vs 1.93 plus/minus 0.25%; p<0.01) and mRNA (0.48 plus/minus 0.09 vs 0.29 plus/minus 0.08 (5beta-reductase/U1); p<0.01) were higher in obese mice. In obese mice 11HSD1 activity was increased in epididymal (68.9 plus/minus 6.2 vs 43.1 plus/minus 7.3%; p=0.01) and omental (18.02 plus/minus 7.8 vs 1.9 plus/minus 0.5%; p=0.01) adipose tissue, but not different in skeletal muscle (6.3 plus/minus 0.8 vs 7.9 plus/minus 1.1; p=0.25). 5Beta-reductase activity was not detected in these other tissues.

In summary, these results provide evidence for similar tissue specific dysregulation of glucocorticoid metabolism in ob/ob mice as has been observed in idiopathic human obesity and Zucker obese rats. The ob/ob mouse provides a valuable murine model for characterising regulation of altered glucocorticoid metabolism in obesity.

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