Boullu-Ciocca Sandrine, Paulmyer-Lacroix Odile, Fina Frédéric, Ouafik L'Houcine, Alessi Marie-Christine, Oliver Charles, Grino Michel
Service d'Endocrinologie and Centre d'Investigation Clinique, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
Obes Res. 2003 Aug;11(8):925-9. doi: 10.1038/oby.2003.127.
Glucocorticoids may be a pathophysiological mediator for the development of visceral obesity. In obese patients, adipose tissue reactivation of cortisone to cortisol is enhanced. In addition, changes in glucocorticoid receptor (GR) could also be important, either at the central nervous system level, by modulating the negative glucocorticoid feedback, or at a peripheral level, by regulating adipose tissue activity.
Using quantitative reverse transcriptase-polymerase chain reaction, we studied the expression of the GR mRNA isoforms (active, GRalpha; inactive, GRbeta) in circulating mononuclear leukocytes (in which GR shares the same regulation with central nervous system GR) obtained from normal weight women (n = 65) and patients with gluteofemoral (n = 26) or visceral (n = 39) obesity. Using in situ hybridization, we measured GRalpha mRNA levels in adipose tissue from control (n = 10) or obese (n = 15) patients.
The mean alpha/beta ratio was decreased in mononuclear leukocytes from obese patients (2.6, 9.2, and 32.1, respectively). GRalpha mRNA levels were significantly decreased in subcutaneous abdominal adipose tissue obtained from obese patients compared with nonobese ones, suggesting the existence of a downregulation of GR gene expression. This phenomenon was not found in visceral adipose tissue.
This suggests that, in obese patients, the relative insensitivity to the negative glucocorticoid feedback is, at least in part, subsequent to a dysregulation of the GRalpha/GRbeta ratio and that visceral, but not subcutaneous, adipose tissue retains a full capacity to respond to increased local generation of cortisol.
糖皮质激素可能是内脏肥胖发生发展的病理生理介质。在肥胖患者中，脂肪组织将可的松转化为皮质醇的再激活过程增强。此外，糖皮质激素受体（GR）的变化也可能很重要，无论是在中枢神经系统水平通过调节糖皮质激素的负反馈，还是在外周水平通过调节脂肪组织活性。
我们使用定量逆转录聚合酶链反应，研究了从体重正常的女性（n = 65）以及臀股部肥胖（n = 26）或内脏肥胖（n = 39）患者获取的循环单核白细胞（其中GR与中枢神经系统GR具有相同的调节方式）中GR mRNA亚型（活性型，GRα；非活性型，GRβ）的表达。我们使用原位杂交技术，测量了对照患者（n = 10）或肥胖患者（n = 15）脂肪组织中的GRα mRNA水平。
肥胖患者单核白细胞中的平均α/β比值降低（分别为2.6、9.2和32.1）。与非肥胖患者相比，肥胖患者腹部皮下脂肪组织中的GRα mRNA水平显著降低，提示存在GR基因表达下调。在内脏脂肪组织中未发现此现象。
这表明，在肥胖患者中，对糖皮质激素负反馈的相对不敏感至少部分是由于GRα/GRβ比值失调所致，并且内脏脂肪组织而非皮下脂肪组织保留了对局部皮质醇生成增加做出充分反应的能力。
