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首页> 外文期刊>BMC Neuroscience >Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and K ATP channel activation
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Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and K ATP channel activation

机译：瘦素和胰岛素刺激弓形核神经元信号通路：PI3K依赖的肌动蛋白重组和K ATP通道激活

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Background Leptin and insulin are long-term regulators of body weight. They act in hypothalamic centres to modulate the function of specific neuronal subtypes, by altering transcriptional control of releasable peptides and by modifying neuronal electrical activity. A key cellular signalling intermediate, implicated in control of food intake by these hormones, is the enzyme phosphoinositide 3-kinase. In this study we have explored further the linkage between this enzyme and other cellular mediators of leptin and insulin action on rat arcuate nucleus neurones and the mouse hypothalamic cell line, GT1-7. Results Leptin and insulin increased the levels of various phosphorylated signalling intermediates, associated with the JAK2-STAT3, MAPK and PI3K cascades in the arcuate nucleus. Inhibitors of PI3K were shown to reduce the hormone driven phosphorylation through the PI3K and MAPK pathways. Using isolated arcuate neurones, leptin and insulin were demonstrated to increase the activity of KATP channels in a PI3K dependent manner, and to increase levels of PtdIns(3,4,5)P3. KATP activation by these hormones in arcuate neurones was also sensitive to the presence of the actin filament stabilising toxin, jasplakinolide. Using confocal imaging of fluorescently labelled actin and direct analysis of G- and F-actin concentration in GT1-7 cells, leptin was demonstrated directly to induce a re-organization of cellular actin, by increasing levels of globular actin at the expense of filamentous actin in a PI3-kinase dependent manner. Leptin stimulated PI3-kinase activity in GT1-7 cells and an increase in PtdIns(3,4,5)P3 could be detected, which was prevented by PI3K inhibitors. Conclusions Leptin and insulin mediated phosphorylation of cellular signalling intermediates and of KATP channel activation in arcuate neurones is sensitive to PI3K inhibition, thus strengthening further the likely importance of this enzyme in leptin and insulin mediated energy homeostasis control. The sensitivity of leptin and insulin stimulation of KATP channel opening in arcuate neurones to jasplakinolide indicates that cytoskeletal remodelling may be an important contributor to the cellular signalling mechanisms of these hormones in hypothalamic neurones. This hypothesis is reinforced by the finding that leptin induces actin filament depolymerization, in a PI3K dependent manner in a mouse hypothalamic cell line.
机译：背景技术瘦素和胰岛素是体重的长期调节剂。它们在下丘脑中心起作用，通过改变可释放肽的转录控制并通过改变神经电活动来调节特定神经元亚型的功能。涉及这些激素控制食物摄入的关键细胞信号传导中间产物是磷酸肌醇3-激酶。在这项研究中，我们进一步探索了该酶与瘦素的其他细胞介体之间的联系，以及胰岛素对大鼠弓形核神经元和小鼠下丘脑细胞系GT1-7的作用。结果瘦素和胰岛素增加了弓形核中与JAK2-STAT3，MAPK和PI3K级联有关的各种磷酸化信号传导中间产物的水平。已显示PI3K抑制剂可通过PI3K和MAPK途径减少激素驱动的磷酸化。使用分离的弓形神经元，瘦素和胰岛素被证明以PI3K依赖性方式增加K ATP 通道的活性，并增加PtdIns（3,4,5）P 3 < / sub>。这些激素在弓形神经元中对K ATP 的激活对肌动蛋白丝稳定毒素jasplakinolide的存在也很敏感。使用荧光标记的肌动蛋白的共聚焦成像并直接分析GT1-7细胞中G-和F-肌动蛋白的浓度，表明瘦蛋白可以通过增加球状肌动蛋白的水平而以丝状肌动蛋白为代价直接诱导细胞肌动蛋白的重组。以PI3激酶依赖性方式。瘦素刺激了GT1-7细胞的PI3激酶活性，并检测到PtdIns（3,4,5）P 3 的增加，这被PI3K抑制剂阻止。结论弓形神经元中瘦素和胰岛素介导的细胞信号传导中间产物的磷酸化和K ATP 通道激活对PI3K抑制敏感，因此进一步增强了该酶在瘦素和胰岛素介导的能量稳态中的重要性。瘦素和胰岛素刺激弓形神经元中K ATP 通道的开放对jasplakinolide的敏感性表明，细胞骨架重塑可能是这些激素在下丘脑神经元中的细胞信号传导机制的重要贡献。通过在小鼠下丘脑细胞系中以PI3K依赖性方式发现瘦素诱导肌动蛋白丝解聚，这一假设得到了加强。

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