Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.
Spexin ameliorates skeletal muscle insulin resistance through activation of GAL2 receptor.
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DOI：
10.1016/j.ejphar.2021.174731
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发表时间：
2021-12
影响因子：
5
通讯作者：
Mei Yu;Mengyuan Wang;Shangwhan Han;Long Han;Yue Kan;Juan Zhao;Xi-zhong Yu;Jing Yan;Yu Jin-Yu-J
中科院分区：
文献类型：
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作者：
Mei Yu;Mengyuan Wang;Shangwhan Han;Long Han;Yue Kan;Juan Zhao;Xi-zhong Yu;Jing Yan;Yu Jin-Yu-J
骨骼肌是参与能量消耗和葡萄糖代谢的主要组织。虽然我们和其他研究结果表明spexin可以减少食物摄入和肥胖，但spexin对骨骼肌葡萄糖代谢的具体代谢作用尚不清楚。本研究的目的是研究spexin是否可以减轻肥胖诱导的骨骼肌胰岛素抵抗，并探讨其可能的机制。用spexin（200、400、800 nM）分别处理L 6分化的肌管12 h，同时加入或不加入M871（800 nM）。此外，在这项研究中，用800 nM spexin处理甘丙肽2型（GAL 2）受体敲低的肌管12 h。本研究结果表明，spexin逆转高脂饮食小鼠的高血糖和葡萄糖耐受不良以及胰岛素耐受不良和胰岛素抵抗。此外，spexin显著增加过氧化物酶体增殖物激活受体γ共激活因子1 α（PGC-1α）的表达和去乙酰化，并通过p38丝裂原活化蛋白激酶（P38 MAPK）和蛋白激酶B（AKT）激活进一步触发葡萄糖转运蛋白4（GLUT 4）的表达和运输。更重要的是，GAL 2受体拮抗剂或GAL 2受体沉默可消除spexin对肌管葡萄糖消耗相关基因的上调作用。总之，我们的研究结果提供了一个新的见解，spexin可以防止胰岛素抵抗，并增加葡萄糖消耗骨骼肌主要通过激活GAL 2/GLUT 4信号通路。Spexin可能成为临床治疗高血糖和胰岛素抵抗的新靶点。
Skeletal muscle is a principal tissue involved in energy expenditure and glucose metabolism. Although the results of our and other studies show that spexin could decrease food intake and obesity, the specific metabolic effect of spexin on glucose metabolism of skeletal muscle is still unclear. The aim of this study is to investigate whether spexin might mitigate obesity-induced insulin resistance in skeletal muscles and to explore its underlying mechanisms. The high fat diet-fed mice were treated with 50 μg/kg/d spexin for 21 consecutive days, and the differentiated myotubes of L6 were treated with spexin (200, 400, 800 nM) in the absence or presence of M871 (800 nM) for 12 h respectively. Besides, the galanin type 2 (GAL2) receptor knockdown myotubes were treated with 800 nM spexin for 12 h in this study. The present findings showed that spexin reversed hyperglycemia and glucose intolerance as well as insulin intolerance and insulin resistance in the mice fed with high fat diet. Furthermore, spexin markedly augmented the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) expression and deacetylation, and further triggered glucose transporter 4 (GLUT4) expression and trafficking in myotubes through p38 mitogen-activated protein kinase (P38MAPK) and protein kinase B (AKT) activation. More importantly, the elevation of glucose consumption related genes by spexin were abolished by GAL2 receptor antagonist or silencing of GAL2 receptor in myotubes. In conclusion, our findings provide a novel insight that spexin can protect against insulin resistance and increase glucose consumption in skeletal muscles mainly through activation of GAL2/GLUT4 signal pathway. Spexin might therefore be a novel therapeutic target for hyperglycemia and insulin resistance in clinic.