Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATP channel activation.
Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATP channel activation.
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DOI：
10.1186/1471-2202-5-54
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发表时间：
2004-12-06
期刊：
影响因子：
2.4
通讯作者：
Ashford ML
中科院分区：
文献类型：
--
作者：
Mirshamsi S;Laidlaw HA;Ning K;Anderson E;Burgess LA;Gray A;Sutherland C;Ashford ML
瘦素和胰岛素是体重的长期调节因素。它们在下丘脑中枢起作用，通过改变可释放肽的转录控制和改变神经元的电活动来调节特定神经元亚型的功能。一种关键的细胞信号传递媒介，与这些激素控制食物摄入量有关，是磷脂酰肌醇3-激酶。在这项研究中，我们进一步探索了该酶与瘦素和胰岛素对大鼠弓状核神经元和小鼠下丘脑细胞系GT1-7作用的其他细胞介质之间的联系。瘦素和胰岛素增加了弓状核中与JAK2-STAT3、MAPK和PI3K级联相关的各种磷酸化信号中间产物的水平。PI3K的抑制剂被证明通过PI3K和MAPK途径减少激素驱动的磷酸化。在分离的弓状神经元上，瘦素和胰岛素以PI3K依赖的方式增加KATP通道的活性，并增加PtdIns(3，4，5)P3的水平。这些激素对弓状神经元中KATP的激活对肌动蛋白细丝稳定毒素jasplakinolide的存在也很敏感。通过荧光标记的肌动蛋白的共聚焦成像和对GT1-7细胞中G-和F-肌动蛋白浓度的直接分析，瘦素被证明直接诱导细胞肌动蛋白的重组，其方式是以PI3-激酶依赖的方式增加球状肌动蛋白的水平，而牺牲丝状肌动蛋白的水平。瘦素可刺激GT1-7细胞的PI3-激酶活性，并可检测到PtdIns(3，4，5)P3的增加，这一作用可被PI3K抑制剂所阻止。瘦素和胰岛素介导的细胞信号中间产物的磷酸化和弓状神经元中KATP通道的激活对PI3K抑制很敏感，从而进一步加强了该酶在瘦素和胰岛素介导的能量稳态控制中的可能重要性。Jasplakinolide对Leptin和胰岛素刺激弓状神经元KATP通道开放的敏感性表明，细胞骨架重构可能是下丘脑神经元中这些激素的细胞信号机制的重要贡献。瘦素以PI3K依赖的方式在小鼠下丘脑细胞系中诱导肌动蛋白细丝解聚，这一发现强化了这一假设。
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. 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. 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.
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4.8
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