Sestrin 2 induces autophagy and attenuates insulin resistance by regulating AMPK signaling in C2C12 myotubes
Sestrin 2 induces autophagy and attenuates insulin resistance by regulating AMPK signaling in C2C12 myotubes
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Sestrin 2 通过调节 C2C12 肌管中的 AMPK 信号传导诱导自噬并减弱胰岛素抵抗
DOI：
10.1016/j.yexcr.2017.03.023
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发表时间：
2017-05-01
影响因子：
3.7
通讯作者：
Fu, Li
中科院分区：
文献类型：
--
作者：
Li, Huige;Liu, Sujuan;Fu, Li
骨骼肌中胰岛素刺激的葡萄糖摄取受损在胰岛素抵抗（IR）的发展中起关键作用，然而该过程的确切机制仍不清楚。最近，进化上保守的、应激诱导蛋白Sestrin2（Sesn2）被认为在肥胖诱导的IR和糖尿病中起保护作用。Sesn2的激活可能激活AMP活化蛋白激酶（AMPK），同时抑制哺乳动物雷帕霉素靶蛋白（mTOR），这最终可能导致自噬诱导。鉴于自噬通过调节能量稳态和代谢对生理和病理调节过程的潜在保护作用，我们研究了Sesn2对棕榈酸诱导的胰岛素抵抗C2C12肌管中胰岛素信号通路成分和胰岛素刺激的葡萄糖摄取的影响。我们发现Sesn2有效地恢复了受损的胰岛素信号。此外，棕榈酸作用下自噬活性降低，而在此情况下Sesn2显著逆转了棕榈酸抑制的自噬信号。我们的研究结果进一步表明，Sesn2诱导的自噬通过激活AMPK信号有助于恢复受损的胰岛素信号。即使存在棕榈酸，Sesn2的上调也可通过AMPK依赖的自噬激活维持胰岛素敏感性和葡萄糖代谢。
Impaired insulin-stimulated glucose uptake in skeletal muscle serves a critical role in the development of insulin resistance (IR), whereas the precise mechanism of the process remains unknown. Recently, the evolutionarily conserved, stress-inducible protein Sestrin2 (Sesn2) has been proposed to play a protective role against obesity induced IR and diabetes. Activation of Sesn2 may activate AMP-activated protein kinase (AMPK) accompanied by suppression of mammalian target of rapamycin (mTOR), which may ultimately lead to autophagy induction. In view of the potential protective effects of autophagy on the physiological and the pathological regulatory processes via the regulation of energy homeostasis and metabolism, we investigated the effects of Sesn2 on the components of the insulin signaling pathway and insulin-stimulated glucose uptake in palmitate-induced insulin-resistant C2C12 myotubes. We showed that Sesn2 effectively restored the impaired insulin signaling. Moreover, autophagic activity decreased in response to palmitate, whereas Sesn2 significantly reversed the palmitate-suppressed autophagic signaling in this context. Our findings further revealed that Sesn2-induced autophagy contributed to restore the impaired insulin signaling through the activation of AMPK signal. Even in the presence of palmitate, Sesn2 up-regulation maintained insulin sensitivity and glucose metabolism via AMPK-dependent autophagic activation.