Livingstone Dawn E W, Grassick Sarah L, Currie Gillian L, Walker Brian R, Andrew Ruth
Endocrinology Unit, Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, UK.
J Endocrinol. 2009 May;201(2):211-8. doi: 10.1677/JOE-09-0003. Epub 2009 Feb 17.
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.
在肥胖人群中，11β-羟基类固醇脱氢酶1型（11β-HSD1）介导的糖皮质激素代谢以及A环还原（由5α-和5β-还原酶介导）以组织特异性方式失调。这些变化在瘦素抵抗的肥胖Zucker大鼠中得到重现，但在高脂喂养的Wistar大鼠中未观察到。来自小鼠模型的最新数据表明，这种差异可能反映了瘦素信号传导的差异。因此，我们比较了瘦素缺乏和抵抗小鼠模型中的糖皮质激素代谢。在12周龄时研究了雄性ob/ob和db/db小鼠及其各自的同窝对照（每组n = 10 - 12）。对速冻组织中的酶活性和mRNA表达进行定量。ob/ob和db/db小鼠中肥胖时类固醇代谢改变途径的模式相似。在肝脏中，肥胖小鼠的5β-还原酶活性和mRNA增加，11β-HSD1降低，而5α-还原酶1（5αR1）mRNA未改变。在内脏脂肪库中，肥胖时不表达5β-还原酶，11β-HSD1活性增加，5αR1 mRNA未改变。相比之下，在皮下脂肪组织中，11β-HSD1和5αR1 mRNA降低。在ob/ob和db/db肥胖小鼠模型之间未发现系统性差异，这表明通过Ob受体短剪接变体的瘦素信号传导变化不会导致糖皮质激素代谢失调。
