title: Dysregulation of glucocorticoid metabolism in murine obesity: comparable effects of leptin resistance and deficiency.
abstract: In obese humans, metabolism of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) and A-ring reduction (by 5 alpha- and 5 beta-reductases) is dysregulated in a tissue specific manner. These changes have been recapitulated in leptin resistant obese Zucker rats but were not observed in high-fat fed Wistar rats. Recent data from mouse models suggest that such discrepancies may reflect differences in leptin signalling. We therefore compared glucocorticoid metabolism in murine models of leptin deficiency and resistance. Male ob/ob and db/db mice and their respective littermate controls (n=10-12/group) were studied at the age of 12 weeks. Enzyme activities and mRNA expression were quantified in snap-frozen tissues. The patterns of altered pathways of steroid metabolism in obesity were similar in ob/ob and db/db mice. In liver, 5 beta-reductase activity and mRNA were increased and 11 beta-HSD1 decreased in obese mice, whereas 5 alpha-reductase 1 (5 alpha R1) mRNA was not altered. In visceral adipose depots, 5 beta-reductase was not expressed, 11 beta-HSD1 activity was increased and 5 alpha R1 mRNA was not altered in obesity. By contrast, in subcutaneous adipose tissue 11 beta-HSD1 and 5 alpha R1 mRNA were decreased. Systematic differences were not found between ob/ob and db/db murine models of obesity, suggesting that variations in leptin signalling through the short splice variant of the Ob receptor do not contribute to dysregulation of glucocorticoid metabolism.
authors.affiliation: Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Dawn E W
authors.initials: DE
authors.lastname: Livingstone
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Grassick
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Currie
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance / Q000235:genetics*; D005938:Glucocorticoids / Q000378:metabolism*; D020738:Leptin / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D020738:Leptin; D054411:Receptors, Leptin