Jing Yu-Hong, Zhang Lang, Gao Li-Ping, Qi Chu-Chu, Lv Dan-Dan, Song Yan-Feng, Yin Jie, Wang De-Gui
Institute of Anatomy and Histology and Embryology, Neuroscience, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Neuro Endocrinol Lett. 2017 Feb;38(1):27-37.
The hypothalamus regulates metabolism and feeding behavior by perceiving the levels of peripheral insulin. However, little is known about the hypothalamic changes after aberrant metabolism. In this study, we investigated the changes of insulin and autophagy relevant signals of hypothalamus under diabetes mellitus.
C57B/L mice were injected with low-dose streptozotocin (STZ) and fed with high-fat diet to induce type 2 diabetes mellitus. In vitro, PC12 cells were treated with oleic acid to mimic lipotoxicity.
Results showed that the cholesterol level in the hypothalamus of the diabetic mice was higher than that of the normal mice. The expression of insulin receptors and insulin receptor substrate-1 were downregulated and the number of Fluoro-Jade C positive cells significantly increased in the hypothalamic arcuate nucleus of the diabetic mice. Furthermore, Upregulation of mammalian target of rapamycin (mTOR) and downregulation of LC 3II were obvious in the hypothalamus of the diabetic mice. In vitro, results showed that high-lipid caused PC12 cell damage and upregulated LC3 II expression. Pretreatment of cells with 3-methyladenine evidently downregulated LC3 II expression and aggravated PC12 cell death under high lipid conditions. By contrast, pretreatment of cells with rapamycin upregulated LC3 II expression and ameliorated PC12 cell death caused by lipotoxicity.
These results demonstrate that autophagy activation confers protection to neurons under aberrant metabolism and that autophagy dysfunction in the hypothalamus occurs in the chronic metabolic disorder such as T2DM.
下丘脑通过感知外周胰岛素水平来调节新陈代谢和摄食行为。然而，关于代谢异常后下丘脑的变化知之甚少。在本研究中，我们调查了糖尿病状态下下丘脑胰岛素及自噬相关信号的变化。
给C57B/L小鼠注射低剂量链脲佐菌素（STZ）并给予高脂饮食以诱导2型糖尿病。在体外，用油酸处理PC12细胞以模拟脂毒性。
结果显示，糖尿病小鼠下丘脑的胆固醇水平高于正常小鼠。糖尿病小鼠下丘脑弓状核中胰岛素受体和胰岛素受体底物-1的表达下调，氟玉髓C阳性细胞数量显著增加。此外，糖尿病小鼠下丘脑雷帕霉素靶蛋白（mTOR）上调而微管相关蛋白1轻链3II（LC 3II）下调明显。在体外，结果显示高脂导致PC12细胞损伤并上调LC3 II表达。用3-甲基腺嘌呤预处理细胞在高脂条件下明显下调LC3 II表达并加重PC12细胞死亡。相比之下，用雷帕霉素预处理细胞上调LC3 II表达并改善脂毒性引起的PC12细胞死亡。
这些结果表明自噬激活在代谢异常情况下为神经元提供保护，且下丘脑自噬功能障碍发生于诸如2型糖尿病等慢性代谢紊乱中。
