Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus - A key mediator of insulin-induced anorexia
Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus - A key mediator of insulin-induced anorexia
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DOI：
10.2337/diabetes.52.2.227
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发表时间：
2003-02-01
期刊：
影响因子：
7.7
通讯作者：
Schwartz, MW
中科院分区：
文献类型：
--
作者：
Niswender, KD;Morrison, CD;Schwartz, MW
在外周组织中，胰岛素信号通路涉及胰岛素受体底物(IRS)-磷脂酰肌醇3-激酶（PI3K）酶系统的激活。在下丘脑中，胰岛素与瘦素一起作为脂肪传入信号发挥作用，对调节身体脂肪储存和肝脏葡萄糖代谢很重要。为了验证下丘脑胰岛素作用涉及细胞内PI3K信号传导的假设，我们使用组织化学和生化方法来确定胰岛素对下丘脑IRS-PI3K活性的影响。在这里，我们报道胰岛素诱导胰岛素受体和IRS-1和-2的酪氨酸磷酸化，增加活化的IRS-1和-2与PI3K调控亚基的结合，并激活PI3K的下游靶点蛋白激酶B/Akt。利用免疫组织化学技术检测PI3K活性的主要产物pi3,4,5 -三磷酸，我们进一步证明，在弓形核中，胰岛素诱导的PI3K活性优先发生在含有IRS-2的细胞内。最后，我们发现胰岛素的食物摄取量降低作用可以通过两种PI3K抑制剂中的任何一种在没有独立摄食效应的剂量下在脑室内输注而逆转。这些发现支持了IRS-PI3K通路是弓状核中胰岛素作用的中介的假设，并结合最近瘦素激活下丘脑PI3K信号的证据，为胰岛素和瘦素信号之间的神经元交叉对话提供了一种合理的机制。
In peripheral tissues, insulin signaling involves activation of the insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI3K) enzyme system. In the hypothalamus, insulin functions with leptin as an afferent adiposity signal important for the regulation of body fat stores and hepatic glucose metabolism. To test the hypothesis that hypothalamic insulin action involves intracellular PI3K signaling, we used histochemical and biochemical methods to determine the effect of insulin on hypothalamic IRS-PI3K activity. Here, we report that insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3K, and activates protein kinase B/Akt, a downstream target of PI3K. Using an immunohistochemical technique to detect PI 3,4,5-triphosphate, the main product of PI3K activity, we further demonstrate that in the arcuate nucleus, insulin-induced PI3K activity occurs preferentially within cells that contain IRS-2. Finally, we show that the food intake-lowering effects of insulin are reversed by intracerebroventricular infusion of either of two PI3K inhibitors at doses that have no independent feeding effects. These findings support the hypothesis that the IRS-PI3K pathway is a mediator of insulin action in the arcuate nucleus and, combined with recent evidence that leptin activates PI3K signaling in the hypothalamus, provide a plausible mechanism for neuronal cross-talk between insulin and leptin signaling.