Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner
Prior AICAR Stimulation Increases Insulin Sensitivity in Mouse Skeletal Muscle in an AMPK-Dependent Manner
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DOI：
10.2337/db14-1402
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发表时间：
2015-06-01
期刊：
影响因子：
7.7
通讯作者：
Wojtaszewski, Jorgen F. P.
中科院分区：
文献类型：
--
作者：
Kjobsted, Rasmus;Treebak, Jonas T.;Wojtaszewski, Jorgen F. P.
急性运动通过胰岛素不依赖型机制增加骨骼肌的葡萄糖摄取。在运动后的一段时间内，胰岛素对葡萄糖摄取增加的敏感性得到增强。支持这一现象的分子机制尚不清楚，但似乎与细胞表面GLUT4丰度的增加有关。虽然近端胰岛素信号的增加似乎并不能介导这种效应，但TBC1 D4磷酸化的升高似乎发挥了作用，TBC1 D4是胰岛素（Akt）和运动（AMPK）信号的下游靶点。本研究的主要目的是确定AMPK激活是否会增加骨骼肌胰岛素敏感性。我们发现先前的AICAR刺激野生型小鼠肌肉增加胰岛素敏感性以刺激葡萄糖摄取。然而，在骨骼肌AMPK活性降低或消退的小鼠中没有观察到这一点。此外，先前的AICAR刺激仅在野生型肌肉中增强了胰岛素刺激的TBC1D4在Thr（649）和Ser（711）的磷酸化。这些磷酸化事件与葡萄糖摄取正相关。我们的结果提供证据支持AMPK激活足以增加骨骼肌胰岛素敏感性。此外，TBC1 D4磷酸化可能促进先前AMPK激活的作用，以增强胰岛素对葡萄糖的摄取。
An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve an increased cell surface abundance of GLUT4. While increased proximal insulin signaling does not seem to mediate this effect, elevated phosphorylation of TBC1 D4, a downstream target of both insulin (Akt) and exercise (AMPK) signaling, appears to play a role. The main purpose of this study was to determine whether AMPK activation increases skeletal muscle insulin sensitivity. We found that prior AICAR stimulation of wild-type mouse muscle increases insulin sensitivity to stimulate glucose uptake. However, this was not observed in mice with reduced or ablated AMPK activity in skeletal muscle. Furthermore, prior AICAR stimulation enhanced insulin-stimulated phosphorylation of TBC1D4 at Thr(649) and Ser(711) in wild-type muscle only. These phosphorylation events were positively correlated with glucose uptake. Our results provide evidence to support that AMPK activation is sufficient to increase skeletal muscle insulin sensitivity. Moreover, TBC1 D4 phosphorylation may facilitate the effect of prior AMPK activation to enhance glucose uptake in response to insulin.