Kim Jongwan, Jung Eun Jung, Moon Seong-Su, Seo Minchul
Institute of Medical Research, Dongguk University College of Medicine, Gyeongju, South Korea; Department of Anatomy, Graduate School of Dongguk University College of Medicine, Gyeongju, South Korea.
Department of Biochemistry, Dongguk University College of Medicine, Gyeongju, South Korea.
Biochem Biophys Res Commun. 2015 Dec 25;468(4):793-9. doi: 10.1016/j.bbrc.2015.11.034. Epub 2015 Nov 11.
Hypothalamic endoplasmic reticulum (ER) stress is known to be increased in obesity. Induction of ER stress on hypothalamic neurons has been reported to cause hypothalamic neuronal apoptosis and malfunction of energy balance, leading to obesity. Carbenoxolone is an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor that converts inactive glucocorticoid into an active form. In addition to its metabolic effect via enzyme inhibitory action, carbenoxolone has shown anti-apoptotic activity in several studies. In this study, the direct effects of carbenoxolone on ER stress and cell death in hypothalamic neurons were investigated. Carbenoxolone attenuated tunicamycin induced ER stress-mediated molecules such as spliced XBP1, ATF4, ATF6, CHOP, and ROS generation. In vivo study also revealed that carbenoxolone decreased tunicamycin-induced ER stress in the hypothalamus. In conclusion, the results of this study show that carbenoxolone has protective effects against tunicamycin induced-ER stress and apoptosis in hypothalamic neurons, suggesting its direct protective effects against obesity. Further study is warranted to clarify the effects of carbenoxolone on hypothalamic regulation of energy balance in obesity.
已知肥胖症患者下丘脑内质网（ER）应激会增加。据报道，下丘脑神经元内质网应激的诱导会导致下丘脑神经元凋亡和能量平衡功能紊乱，进而引发肥胖。甘草次酸是一种11β-羟基类固醇脱氢酶1型（11β-HSD1）抑制剂，可将无活性的糖皮质激素转化为活性形式。除了通过酶抑制作用产生代谢效应外，甘草次酸在多项研究中还显示出抗凋亡活性。在本研究中，研究了甘草次酸对下丘脑神经元内质网应激和细胞死亡的直接影响。甘草次酸减轻了衣霉素诱导的内质网应激介导分子，如剪接的XBP1、ATF4、ATF6、CHOP以及活性氧的产生。体内研究还表明，甘草次酸可降低衣霉素诱导的下丘脑内质网应激。总之，本研究结果表明，甘草次酸对衣霉素诱导的下丘脑神经元内质网应激和凋亡具有保护作用，提示其对肥胖具有直接保护作用。有必要进一步研究以阐明甘草次酸对肥胖症患者下丘脑能量平衡调节的影响。
