Contribution of glucocorticoid-mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction

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• 作者：Ayumu Hirata ; ^{hirata@endmet.med.osaka-u.ac.jp} ; Norikazu Maeda ; ^{norikazu_maeda@endmet.med.osaka-u.ac.jp} ; Hideaki Nakatsuji ; Aki Hiuge-Shimizu ; Takuya Okada ; Tohru Funahashi ; Iichiro Shimomura
• 关键词：Mineralocorticoid receptor ; Glucocorticoid ; Obesity ; Oxidative stress ; Adiponectin
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：9 March, 2012
• 卷：419
• 期：2
• 页码：182-187
• 文件大小：323 K

摘要

Aims

Mineralocorticoid receptor (MR) blockade ameliorated insulin resistance with improvements in adipocytokine dysregulation, inflammation, and excess of reactive oxygen species (ROS) in obese adipose tissue and adipocytes, but its mechanism has not been clarified. The 11尾-hydroxysteroid dehydrogenase type 1 (11尾-HSD1), producing active glucocorticoids, is highly expressed in adipocytes and glucocorticoids bind to MR with higher affinity than to glucocorticoid receptor (GR). We investigated whether glucocorticoids effect on adipocytokines and ROS through MR in adipocytes. In addition, fat distributions of MR and GR were investigated in human subjects.

Methods and Results

Corticoid receptors and their target genes were examined in adipose tissue of obese db/db mice. 3T3-L1 adipocytes were treated with glucocorticoids, H₂O₂, MR antagonist eplerenone (EP), GR antagonist RU486 (RU), MR-siRNA, and/or N-acetylcysteine. Human adipose tissues were obtained from seven patients who underwent abdominal surgery. The mRNA levels of MR and its target gene were higher in db/db mice than in control db/m + mice. In 3T3-L1 adipocytes, glucocorticoids, similar to H₂O₂, caused the dysregulation of mRNA levels of various genes related to adipocytokines and the increase of intracellular ROS. Such changes were rectified by MR blockade, not by GR antagonist. In human fat, MR mRNA level was increased in parallel with the increase of body mass index (BMI) and its increase was more significant in visceral fat, while there were no apparent correlations of GR mRNA level to BMI or fat distribution.

Conclusion

Glucocorticoid-MR pathway may contribute to the obesity-related adipocytokine dysregulation and adipose ROS.