Rask E, Olsson T, Söderberg S, Andrew R, Livingstone D E, Johnson O, Walker B R
Departments of Public Health and Clinical Medicine, Umeå University Hospital, Sweden.
J Clin Endocrinol Metab. 2001 Mar;86(3):1418-21. doi: 10.1210/jcem.86.3.7453.
Cortisol has been implicated as a pathophysiological mediator in idiopathic obesity, but circulating cortisol concentrations are not consistently elevated. The tissue-specific responses to cortisol may be influenced as much by local prereceptor metabolism as by circulating concentrations. For example, in liver and adipose tissue cortisol is regenerated from inactive cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). In obese Zucker rats 11beta-HSD1 activity is reduced in liver but enhanced in adipose tissue. This study addressed whether the same tissue-specific disruption of cortisol metabolism occurs in human obesity. 34 men were recruited from the MONICA population study in Northern Sweden to represent a wide range of body composition and insulin insensitivity. Plasma cortisol was measured at 0830h and 1230h, after overnight low-dose dexamethasone suppression, after intravenous corticotropin releasing hormone (CRH), and after oral cortisone administration. Urinary cortisol metabolites were measured in a 24 h sample. A subcutaneous fat biopsy was obtained from 16 participants to measure cortisol metabolism in vitro. Higher body mass index was associated with increased total cortisol metabolite excretion (r = 0.47, p < 0.01), but lower plasma cortisol at 1230 h and after dexamethasone, and no difference in response to CRH. Obese men excreted a greater proportion of glucocorticoid as metabolites of cortisone rather than cortisol (r = 0.43, p < 0.02), and converted less cortisone to cortisol after oral administration (r = 0.49, p < 0.01), suggesting impaired hepatic 11beta-HSD1 activity. By contrast, in vitro 11beta-HSD1 activity in subcutaneous adipose tissue was markedly enhanced in obese men (r = 0.66, p < 0.01). We conclude that in obesity, reactivation of cortisone to cortisol by 11beta-HSD1 in liver is impaired, so that plasma cortisol levels tend to fall, and there may be a compensatory increase in cortisol secretion mediated by a normally functioning hypothalamic-pituitary-adrenal axis. However, changes in 11beta-HSD1 are tissue-specific: strikingly enhanced reactivation of cortisone to cortisol in subcutaneous adipose tissue may exacerbate obesity; and it may be beneficial to inhibit this enzyme in adipose tissue in obese patients.
皮质醇被认为是特发性肥胖中的一种病理生理介质，但循环中的皮质醇浓度并非持续升高。皮质醇的组织特异性反应可能同样受到局部受体前代谢和循环浓度的影响。例如，在肝脏和脂肪组织中，皮质醇可通过11β - 羟基类固醇脱氢酶1型（11β - HSD1）从无活性的可的松再生而来。在肥胖的 Zucker 大鼠中，肝脏中的11β - HSD1活性降低，但脂肪组织中的活性增强。本研究探讨了人类肥胖中是否会出现相同的皮质醇代谢组织特异性破坏。从瑞典北部的莫妮卡人群研究中招募了34名男性，以代表广泛的身体组成和胰岛素敏感性。在上午0830时和1230时、过夜低剂量地塞米松抑制后、静脉注射促肾上腺皮质激素释放激素（CRH）后以及口服可的松后测量血浆皮质醇。在24小时样本中测量尿皮质醇代谢产物。从16名参与者身上获取皮下脂肪活检样本以体外测量皮质醇代谢。较高的体重指数与总皮质醇代谢产物排泄增加相关（r = 0.47，p < 0.01），但在1230时和地塞米松后血浆皮质醇较低，且对CRH的反应无差异。肥胖男性排泄的糖皮质激素中，可的松代谢产物的比例高于皮质醇（r = 0.43，p < 0.02），口服给药后将可的松转化为皮质醇的比例较低（r = 0.49，p < 0.01），提示肝脏11β - HSD1活性受损。相比之下，肥胖男性皮下脂肪组织中的体外11β - HSD1活性明显增强（r = 0.66，p < 0.01）。我们得出结论，在肥胖中，肝脏中由11β - HSD1将可的松重新激活为皮质醇的过程受损，导致血浆皮质醇水平趋于下降，并且可能由正常功能的下丘脑 - 垂体 - 肾上腺轴介导皮质醇分泌出现代偿性增加。然而，11β - HSD1的变化具有组织特异性：皮下脂肪组织中可的松重新激活为皮质醇的显著增强可能会加重肥胖；在肥胖患者的脂肪组织中抑制这种酶可能是有益的。
