DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling
DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling
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DOCK5 通过靶向 mTORC1 信号调节能量平衡和肝脏胰岛素敏感性
DOI：
10.15252/embr.201949473
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发表时间：
2019-12-29
期刊：
影响因子：
7.7
通讯作者：
Yang, Gangyi
中科院分区：
文献类型：
--
作者：
Lai, Yerui;Zhao, Anjiang;Yang, Gangyi
细胞质分裂5献身基因（DOCK5）与肥胖有关。然而，DOCK5导致肥胖的机制仍然完全未知。本研究表明，在胰岛素抵抗（IR）状态下，肝脏DOCK5表达显著降低。在高脂饮食（HFD）下，小鼠中DOCK5的缺失减少了能量消耗，促进了肥胖，增加了IR，失调了葡萄糖代谢，并激活了mTOR (Raptor)/S6K1通路。DOCK5在肝细胞中的过表达抑制糖异生基因的表达，增加胰岛素受体（InsR）和Akt磷酸化水平。DOCK5过表达也抑制mTOR/S6K1磷酸化，降低猛禽蛋白表达水平。在缺乏DOCK5的肝细胞中观察到相反的效果。重要的是，在肝脏特异性Raptor基因敲除小鼠和相关肝细胞中，腺相关病毒（AAV8）或腺病毒介导的DOCK5基因敲除对葡萄糖代谢和胰岛素信号传导的影响在很大程度上被消除。此外，DOCK5 - raptor的相互作用对于DOCK5介导的肝糖生成（HGP）的调节是不可或缺的。因此，DOCK5作为Raptor的调节因子来控制肝脏胰岛素活性和葡萄糖稳态。
The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high‐fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5‐deficient hepatocytes. Importantly, in liver‐specific Raptor knockout mice and associated hepatocytes, the effects of an adeno‐associated virus (AAV8)‐ or adenovirus‐mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5–Raptor interaction is indispensable for the DOCK5‐mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.