Central leptin action improves skeletal muscle AKT, AMPK, and PGC1α activation by hypothalamic PI3K-dependent mechanism
Central leptin action improves skeletal muscle AKT, AMPK, and PGC1α activation by hypothalamic PI3K-dependent mechanism
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DOI：
10.1016/j.mce.2009.08.007
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发表时间：
2010-01-15
影响因子：
4.1
通讯作者：
Torsoni, Marcio A.
中科院分区：
文献类型：
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作者：
Roman, Erika A. F. R.;Reis, Daniel;Torsoni, Marcio A.
中枢瘦素的作用需要PI3K活性来调节葡萄糖稳态和外周代谢。然而，这一现象背后的机制尚不清楚。我们假设下丘脑PI3K活性对骨骼肌(SM)中AMP激活的蛋白激酶(AMPK)/乙酰辅酶A羧基酶(ACC)途径、PGC1a和AKT的调节是重要的。为了解决这个问题，我们将瘦素注射到大鼠的侧脑室。脑室注射瘦素以时间依赖的方式激活下丘脑JAK2和AKT。中枢瘦素可改善比目鱼肌的葡萄糖耐量(GTT)，增加PGC1α的表达，以及AKT、AMPK、ACC和JAK2的磷酸化。先前脑室注射LY294002或心得安(IP)可阻断这些效应。我们认为，下丘脑PI3K通路的激活在瘦素诱导的AKT磷酸化以及通过AMPK和PGC1α激活的分解代谢通路中起重要作用。因此，下丘脑中瘦素信号转导PI3K通路的缺陷可能与饮食诱导肥胖相关的外周胰岛素抵抗有关。(C)2009爱思唯尔爱尔兰有限公司。保留所有权利。
Central leptin action requires PI3K activity to modulate glucose homeostasis and peripheral metabolism. However, the mechanism behind this phenomenon is not clearly understood. We hypothesize that hypothalamic PI3K activity is important for the modulation of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway, PGC1 alpha, and AKT in skeletal muscle (SM). To address this issue, we injected leptin into the lateral ventricle of rats. Hypothalamic JAK2 and AKT were activated by intracerebroventricular (ICV) injection of leptin in a time-dependent manner. Central leptin improved tolerance to glucose (GTT), increased PGC1 alpha expression, and AKT, AMPK, ACC and JAK2 phosphorylation in the soleus muscle. Previous ICV administration of either LY294002 or propranolol (IP) blocked these effects. We concluded that the activation of the hypothalamic PI3K pathway is important for leptin-induced AKT phosphorylation, as well as for active catabolic pathway through AMPK and PGC1 alpha in SM. Thus, a defective leptin signalling PI3K pathway in the hypothalamus may contribute to peripheral resistance to insulin associated to diet-induced obesity. (C) 2009 Elsevier Ireland Ltd. All rights reserved.