Wake Deborah J, Rask Eva, Livingstone Dawn E W, Söderberg Stefan, Olsson Tommy, Walker Brian R
Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland EH4 2XU.
J Clin Endocrinol Metab. 2003 Aug;88(8):3983-8. doi: 10.1210/jc.2003-030286.
In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance. Using these biopsies, we have now validated this observation by measuring 11HSD1 and GR mRNA and examined the impact on intraadipose cortisol concentrations, putative glucocorticoid regulated adipose target gene expression (angiotensinogen and leptin), and systemic measurements of cortisol metabolism. From aliquots of sc adipose biopsies from 16 men and 16 women we extracted RNA for real-time PCR and steroids for immunoassays. Adipose 11HSD1 mRNA was closely related to 11HSD1 activity [standardized beta coefficient (SBC) = 0.58; P < 0.01], and both were positively correlated with parameters of obesity (e.g. for BMI, SBC = 0.48; P < 0.05 for activity, and SBC = 0.63; P < 0.01 for mRNA) and insulin sensitivity (log fasting plasma insulin; SBC = 0.44; P < 0.05 for activity, and SBC = 0.33; P = 0.09 for mRNA), but neither correlated with urinary cortisol/cortisone metabolite ratios. Adipose GR-alpha and angiotensinogen mRNA levels were not associated with obesity or insulin resistance, but leptin mRNA was positively related to 11HSD1 activity (SBC = 0.59; P < 0.05) and tended to be associated with parameters of obesity (BMI: SBC = 0.40; P = 0.09), fasting insulin (SBC = 0.65; P < 0.05), and 11HSD1 mRNA (SBC = 0.40; P = 0.15). Intraadipose cortisol (142 +/- 30 nmol/kg) was not related to 11HSD1 activity or expression, but was positively correlated with plasma cortisol. These data confirm that idiopathic obesity is associated with transcriptional up-regulation of 11HSD1 in adipose, which is not detected by conventional in vivo measurements of urinary cortisol metabolites and is not accompanied by dysregulation of GR. Although this may drive a compensatory increase in leptin synthesis, whether it has an adverse effect on intraadipose cortisol concentrations and GR-dependent gene regulation remains to be established.
在特发性肥胖中，循环皮质醇水平并未升高，但脂肪组织内皮质醇浓度升高与之相关。11β-羟基类固醇脱氢酶1型（11HSD1）催化无活性的可的松转化为活性皮质醇，从而增强糖皮质激素受体（GR）的激活。在男性和女性队列中，我们已表明，皮下脂肪组织中离体11HSD1活性增加与体内肥胖和胰岛素抵抗相关。利用这些活检样本，我们现在通过测量11HSD1和GR mRNA验证了这一观察结果，并研究了其对脂肪组织内皮质醇浓度、假定的糖皮质激素调节的脂肪靶基因表达（血管紧张素原和瘦素）以及皮质醇代谢的全身测量的影响。从16名男性和16名女性的皮下脂肪活检样本中取出部分样本，我们提取RNA用于实时PCR，并提取类固醇用于免疫测定。脂肪组织11HSD1 mRNA与11HSD1活性密切相关[标准化β系数（SBC）=0.58；P<0.01]，且二者均与肥胖参数（如BMI，活性的SBC=0.48；P<0.05，mRNA的SBC=0.63；P<0.01）和胰岛素敏感性（空腹血浆胰岛素对数；活性的SBC=0.44；P<0.05，mRNA的SBC=0.33；P=0.09）呈正相关，但均与尿皮质醇/可的松代谢物比率无关。脂肪组织GR-α和血管紧张素原mRNA水平与肥胖或胰岛素抵抗无关，但瘦素mRNA与11HSD1活性呈正相关（SBC=0.59；P<0.05），并倾向于与肥胖参数（BMI：SBC=0.40；P=0.09）、空腹胰岛素（SBC=0.65；P<0.05）和11HSD1 mRNA（SBC=0.40；P=0.15）相关。脂肪组织内皮质醇（142±30 nmol/kg）与11HSD1活性或表达无关，但与血浆皮质醇呈正相关。这些数据证实，特发性肥胖与脂肪组织中11HSD1的转录上调相关，这在传统的尿皮质醇代谢物体内测量中未被检测到，且不伴有GR的失调。尽管这可能会促使瘦素合成代偿性增加，但它是否对脂肪组织内皮质醇浓度和GR依赖性基因调节有不利影响仍有待确定。
