Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan.
Biochem Biophys Res Commun. 2012 Mar 9;419(2):182-7. doi: 10.1016/j.bbrc.2012.01.139. Epub 2012 Feb 3.
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 11β-hydroxysteroid dehydrogenase type 1 (11β-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.
Corticoid receptors and their target genes were examined in adipose tissue of obese db/db mice. 3T3-L1 adipocytes were treated with glucocorticoids, H(2)O(2), 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 H(2)O(2), 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.
Glucocorticoid-MR pathway may contribute to the obesity-related adipocytokine dysregulation and adipose ROS.
盐皮质激素受体 (MR) 阻断可改善胰岛素抵抗，其机制可能与肥胖脂肪组织和脂肪细胞中细胞因子失调、炎症和活性氧 (ROS) 过度有关，但这一机制尚未阐明。11β-羟类固醇脱氢酶 1（11β-HSD1）可产生有活性的糖皮质激素，在脂肪细胞中高表达，且糖皮质激素与 MR 的亲和力高于与糖皮质激素受体 (GR) 的亲和力。我们研究了糖皮质激素是否通过脂肪细胞中的 MR 对细胞因子和 ROS 产生影响。此外，还研究了人类脂肪组织中 MR 和 GR 的分布。
检测肥胖 db/db 小鼠脂肪组织中的皮质激素受体及其靶基因。用糖皮质激素、H₂O₂、MR 拮抗剂依普利酮 (EP)、GR 拮抗剂 RU486 (RU)、MR-siRNA 及/或 N-乙酰半胱氨酸处理 3T3-L1 脂肪细胞。从接受腹部手术的 7 名患者中获得人脂肪组织。db/db 小鼠脂肪组织中 MR 及其靶基因的 mRNA 水平高于对照 db/m+mice。在 3T3-L1 脂肪细胞中，糖皮质激素与 H₂O₂ 相似，可导致与细胞因子相关的各种基因的 mRNA 水平失调，并增加细胞内 ROS。这种变化可通过 MR 阻断得到纠正，而不受 GR 拮抗剂的影响。在人脂肪中，MR mRNA 水平随体重指数 (BMI) 的增加而增加，且内脏脂肪的增加更为显著，而 GR mRNA 水平与 BMI 或脂肪分布无明显相关性。
糖皮质激素-MR 途径可能参与肥胖相关的细胞因子失调和脂肪 ROS。
