Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin.
Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin.
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DOI：
10.1172/jci21737
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发表时间：
2004-09
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影响因子：
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通讯作者：
K. Rahmouni;D. Morgan;Gina Morgan;Xuebo Liu;C. Sigmund;A. Mark;W. Haynes
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文献类型：
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作者：
K. Rahmouni;D. Morgan;Gina Morgan;Xuebo Liu;C. Sigmund;A. Mark;W. Haynes
胰岛素在中枢神经系统中的作用产生交感神经系统激活(也称为交感激活)，尽管介导这一过程的神经细胞内机制尚不清楚。我们推测，参与胰岛素受体信号转导的主要途径PI3K和MAPK介导交感神经对胰岛素的反应。大鼠脑室注射胰岛素可增加后肢、棕色脂肪组织、肾上腺和肾脏的多纤维交感神经活性。对下丘脑内侧基底部组织的体外生化研究表明，胰岛素刺激下丘脑胰岛素受体底物-1与PI3K的p85α亚基以及MAPK的p42和p44亚基的酪氨酸磷酸化。为了确定PI3K和/或MAPK是否参与胰岛素介导的交感激活，我们检测了PI3K(LY294002和wortmannin)和MAPK(PD98059和U0126)的特异性抑制剂对胰岛素局部交感反应的影响。有趣的是，阻断PI3K和MAPK对胰岛素的区域交感神经激活有不同的影响。抑制PI3K特异性阻断胰岛素诱导的后肢交感神经激活，而抑制MAPK特异性阻断胰岛素诱导的BAT交感神经激活。然而，对促肾上腺皮质激素释放因子的交感激活不受抑制PI3K和MAPK的影响。这些数据表明，PI3K和MAPK是胰岛素对交感神经系统作用的特异性和区域性的介导物。
The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate-1 with the p85alpha subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.