Modulation of 11,8-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers
Modulation of 11,8-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers
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DOI：
10.1210/jc.2002-020510
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发表时间：
2003-01-01
影响因子：
5.8
通讯作者：
Hochberg, Z
中科院分区：
文献类型：
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作者：
Friedberg, M;Zoumakis, E;Hochberg, Z
糖皮质激素是由11β-羟基类固醇在受体前水平调节的。脱氢酶(11beta-HSD)，可相互转化非活性皮质醇和活性皮质醇。在之前的一项研究中，我们注意到下丘脑肥胖患者的皮质醇/皮质醇代谢产物的比例增加，这表明11β-HSD-1活性增强。在这项体外研究中，我们验证了脂肪11β-HSD-1受下丘脑通过循环激素、交感神经系统神经支配和/或细胞因子调节的假说。从健康的非肥胖者的sc脂肪中提取前脂肪细胞，并在体外分化为成熟脂肪细胞。细胞与几种潜在的效应物孵育，通过测量添加的500 nM可的松到皮质醇的转化率来检测11β-HSD-1的活性。用实时定量聚合酶链式反应检测11beta-HSD-1mRNA的表达，通过测定培养上清液中甘油的浓度来确定脂解作用。促肾上腺皮质激素释放激素下调11β-HSD-1活性，在10(-9)m处作用最强(65+/-10%的对照组；P<；0.001)，并导致脂解减少。同样，ACTH下调11β-HSD-1活性，在10(-9)m处作用最强(65+/-20%；P<；0.05)，并减少中等浓度的甘油。CRH和ACTH均不影响11beta-HSD-1mRNA的表达。在0.6×10(-9)M(140+/-20%；P<；0.001)，肿瘤坏死因子α最大限度地上调11β-HSD-1的活性；同样的细胞因子使11β-HSD-1mRNA水平增加到对照组的3倍，中甘油水平增加到对照组的165+/-14%(P<；0.01)。IL-1β还在0.6x10(-9)M(160+/-33%；P<；0.001)最大程度上调11β-HSD-1活性，并导致甘油水平升高(对照组的159%+/-11%；P<；0.001)。肾上腺素能激动剂中的沙丁胺醇。在10(-7)M时，11β-HSD-1活性上调幅度最大(162±46%；P<；0.02)；可乐定在10(-7)M时下调活性(82+/-15%；P<；0.005)。我们得出结论，下丘脑调节脂肪组织11β-HSD-1的不同介质可能包括CRH、ACTH和α2交感刺激下调11β-HSD-1活性，132交感刺激和细胞因子TNFpha和IL-1β上调该酶。
Glucocorticoids are regulated at the prereceptor level by 11beta-hydroxysteroid. dehydrogenase (11beta-HSD), which interconverts inactive cortisone and active cortisol. In a previous study, we noted that patients with hypothalamic obesity had an increased ratio of cortisol/cortisone metabolites, suggesting enhanced 11beta-HSD-1 activity. In this in vitro study, we tested the hypothesis that adipose 11beta-HSD-1 is regulated by the hypothalamus via circulating hormones, sympathetic nervous system innervation, and/or cytokines. Preadipocytes were retrieved from sc fat from healthy nonobese individuals and differentiated in vitro to mature adipocytes. Cells were incubated with several potential effectors, and the activity of 11beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11beta-HSD-1 mRNA was determined by real-time PCR, whereas lipolytic effects were determined by measuring glycerol concentration in the culture medium. CRH down-regulated 11beta-HSD-1 activity with maximal effect at 10(-9) m (65 +/- 10% of control; P < 0.001) and caused a reduction in lipolysis. Likewise, ACTH down-regulated 11beta-HSD-1 activity with maximal effect at 10(-9) m (65 +/- 20%; P < 0.05) and reduced medium glycerol. Neither CRH nor ACTH affected 11beta-HSD-1 mRNA expression. TNFalpha up-regulated 11beta-HSD-1 activity maximally at 0.6 x 10(-9) M (140 +/- 20%; P < 0.001); the same cytokine increased 11beta-HSD-1 mRNA levels to 3-fold of control (P < 0.05) and increased medium glycerol levels to 165 +/- 14% of control (P < 0.01). IL-1beta also up-regulated 11beta-HSD-1 activity maximally at 0.6 x 10(-9) M (160 +/- 33%; P < 0.001) and caused an increase in glycerol levels (159 +/- 11% of control; P < 0.001). Of the adrenergic agonists, salbutamol. up-regulated 11beta-HSD-1 activity maximally at 10(-7) M (162 +/- 46%; P < 0.02), and clonidine down-regulated it at 10(-7) M (82 +/- 15%; P < 0.005). We conclude that possible distinct hypothalamic mediators regulating adipose tissue 11beta-HSD-1 might include down-regulation of 11beta-HSD-1 activity by CRH, ACTH, and alpha2 sympathetic stimulation, and up-regulation of the enzyme by 132 sympathetic stimulation and by the cytokines TNFalpha and IL-1beta.