Medical Institute of Dongguk University, Gyeongju, South Korea.
Department of Agricultural Biology, National Institute of Agricultural Sciences, Rural Development Administration, Wanju-gun, South Korea.
J Neuroendocrinol. 2018 Mar;30(3):e12580. doi: 10.1111/jne.12580.
The hypothalamus is the regulatory centre of both appetite and energy balance and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 β hydroxysteroid dehydrogenase type1 (11β-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, the link between the role of 11β-HSD1 in the hypothalamus and obesity has yet to be determined. In the present study, embryonal primary hypothalamic neurones and high-fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11β-HSD1 inhibitors both in vitro and in vivo. In hypothalamic neurones, carbenoxolone (a non selecitve 11β-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, i.c.v. administration of carbenoxolone or KR67500 (nonselective and selective 11β-HSD1 inhibitors, respectively) was associated with less weight gain compared to control mice for 24 hours after treatment, presumably by reducing food intake. Furthermore, glucose regulated protein (Grp78), spliced X-box binding protein (Xbp-1s), c/EBP homologous protein (chop) and ER DnaJ homologue protein (Erdj4) expression was decreased in the hypothalami of mice administrated 11β-HSD1 inhibitors compared to controls. Conversely, the phosphorylation of protein kinase B (PKB/Akt), signal transducer and activator of transcription 3 (Stat3), mitogen-activated protein kinase (MAPK/ERK) and S6 kinase1 (S6K1) in the hypothalamus was induced more in mice treated using the same regimes. In conclusion, acute 11β-HSD1 inhibition in the hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1 (mTORC1) signalling.
下丘脑是食欲和能量平衡的调节中心，内质网（ER）应激在肥胖的发病机制中起作用。最近，抑制 11β-羟类固醇脱氢酶 1 型（11β-HSD1）通过减少脂肪量被报道具有抗肥胖作用。然而，11β-HSD1 在下丘脑中的作用与肥胖之间的联系尚未确定。在本研究中，使用胚胎原代下丘脑神经元和高脂肪饮食（HFD）喂养的小鼠，在体外和体内研究了 11β-HSD1 抑制剂的厌食作用。在下丘脑神经元中，Carbenoxolone（一种非选择性 11β-HSD 抑制剂）减轻了 ER 应激和 ER 应激诱导的神经肽改变。在 HFD 小鼠中，与对照组相比，Carbenoxolone 或 KR67500（非选择性和选择性 11β-HSD1 抑制剂，分别）的脑室内给药与治疗后 24 小时内体重增加较少，可能是通过减少食物摄入。此外，与对照组相比，给予 11β-HSD1 抑制剂的小鼠下丘脑的葡萄糖调节蛋白（Grp78）、剪接 X 盒结合蛋白（Xbp-1s）、C/EBP 同源蛋白（chop）和 ER DnaJ 同源蛋白（Erdj4）表达减少。相反，用相同方案处理的小鼠下丘脑的蛋白激酶 B（PKB/Akt）、信号转导和转录激活因子 3（Stat3）、丝裂原激活蛋白激酶（MAPK/ERK）和 S6 激酶 1（S6K1）磷酸化增加。总之，急性下丘脑 11β-HSD1 抑制可通过减少 ER 应激和增加胰岛素、瘦素和哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）信号来减少食物摄入。
