Hirata Ayumu, Maeda Norikazu, Hiuge Aki, Hibuse Toshiyuki, Fujita Koichi, Okada Takuya, Kihara Shinji, Funahashi Tohru, Shimomura Iichiro
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan.
Cardiovasc Res. 2009 Oct 1;84(1):164-72. doi: 10.1093/cvr/cvp191. Epub 2009 Jun 8.
In obesity, chronic low-grade inflammation and overproduction of reactive oxygen species (ROS) in fat contribute to the development of metabolic syndrome. Suppression of inflammation and ROS production in fat may attenuate the metabolic syndrome. Activation of mineralocorticoid receptor (MR) promotes inflammation in heart, kidney, and vasculature via ROS generation. However, the significance of MR in fat remains elusive. Here we investigated whether MR blockade attenuates obesity-related insulin resistance and improves adipocyte dysfunction.
Obese ob/ob and db/db mice were treated with eplerenone, a MR antagonist, for 3 weeks. 3T3-L1 adipocytes were treated with aldosterone or H2O2, with and without eplerenone or MR-siRNA. High levels of MR mRNA were detected in adipose tissue of obese ob/ob and db/db mice. Eplerenone treatment significantly reduced insulin resistance, suppressed macrophage infiltration and ROS production in adipose tissues, and corrected the mRNA levels of obesity-related genes in obese mice. In 3T3-L1 adipocytes, aldosterone and H2O2 increased intracellular ROS levels and MR blockade inhibited such increases. H2O2 and aldosterone resulted in dysregulation of mRNAs of various genes related to ROS and cytokines, whereas MR blockade corrected such changes.
MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.
在肥胖症中，脂肪组织中的慢性低度炎症和活性氧（ROS）的过度产生会导致代谢综合征的发展。抑制脂肪组织中的炎症和ROS产生可能会减轻代谢综合征。盐皮质激素受体（MR）的激活通过ROS的产生促进心脏、肾脏和血管的炎症。然而，MR在脂肪组织中的作用仍不清楚。在此，我们研究了MR阻断是否能减轻肥胖相关的胰岛素抵抗并改善脂肪细胞功能障碍。
肥胖的ob/ob和db/db小鼠用MR拮抗剂依普利酮治疗3周。3T3-L1脂肪细胞用醛固酮或H2O2处理，同时或不同时使用依普利酮或MR-siRNA。在肥胖的ob/ob和db/db小鼠的脂肪组织中检测到高水平的MR mRNA。依普利酮治疗显著降低了胰岛素抵抗，抑制了脂肪组织中的巨噬细胞浸润和ROS产生，并纠正了肥胖小鼠中肥胖相关基因的mRNA水平。在3T3-L1脂肪细胞中，醛固酮和H2O2增加了细胞内ROS水平，而MR阻断抑制了这种增加。H2O2和醛固酮导致与ROS和细胞因子相关的各种基因的mRNA失调，而MR阻断纠正了这种变化。
MR阻断部分通过减少脂肪ROS产生、炎症过程和细胞因子的诱导来减轻肥胖相关的胰岛素抵抗。
