Acute Inhibition of Central c-Jun N-terminal Kinase Restores Hypothalamic Insulin Signalling and Alleviates Glucose Intolerance in Diabetic Mice
Acute Inhibition of Central c-Jun N-terminal Kinase Restores Hypothalamic Insulin Signalling and Alleviates Glucose Intolerance in Diabetic Mice
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DOI：
10.1111/jne.12018
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发表时间：
2013-05-01
影响因子：
3.2
通讯作者：
Tups, A.
中科院分区：
文献类型：
--
作者：
Benzler, J.;Ganjam, G. K.;Tups, A.
下丘脑被认为是调节正常体重和葡萄糖代谢的主要胰岛素靶组织。最近的观察表明，c-Jun-N末端激酶(JNK)信号在肥胖和胰岛素抵抗的发展中起着关键作用，因为在小鼠中，神经元JNK-1的去势可以防止高脂饮食诱导的肥胖(DIO)和能量消耗的增加，以及胰岛素的敏感性。在目前的研究中，我们研究了中枢JNK抑制是否与高脂饮食喂养3周的小鼠和瘦素缺乏小鼠下丘脑胰岛素信号的敏化有关。我们确定了静脉注射是否。注射药物JNK抑制剂(SP600125)可改善受损的血糖稳态。通过免疫组织化学方法，我们首次观察到两种模型小鼠的下丘脑腹内侧核(VMH)和弓状核(ARC)的JNK活性均较正常血糖对照组升高。这表明，JNK在这些区域的上调与葡萄糖耐受和肥胖有关，与瘦素水平无关。急性丙型脑炎。注射SP600125可在30min内改善瘦素缺乏和DIO小鼠的糖耐量。考虑到I.C.V.的急性性。注射，这些影响不能归因于食物摄入量或能量平衡的变化。在下丘脑细胞系中，在瘦素缺乏的小鼠的ARC和VMH中，SP600125抑制JNK持续改善受损的胰岛素信号。这是通过下丘脑细胞系中磷酸胰岛素受体底物-1[IRS-1(Ser612)]蛋白的减少以及ARC和VMH中PIRS-1(Ser612)免疫反应细胞数量的减少来确定的。IRS-1的丝氨酸612磷酸化被认为是负向调节胰岛素信号的。在瘦素缺乏的小鼠中，中枢抑制JNK增加了磷酸化Akt(Ser473)和磷酸化GSK-3(Ser9)免疫反应阳性的细胞数量，这是胰岛素信号传递的重要标志。总而言之，我们的数据表明，中枢JNK的急性抑制改善了受损的葡萄糖稳态，并与下丘脑胰岛素信号的敏化有关。
The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3 (Ser9), which are important markers of insulin signalling. Collectively, our data suggest that the acute inhibition of central JNK improves impaired glucose homeostasis and is associated with sensitisation of hypothalamic insulin signalling.