TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling.
TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling.
复制标题
TUSC5通过调节GLUT4回收来调节胰岛素介导的脂肪组织葡萄糖摄取。
DOI：
10.1016/j.molmet.2015.08.003
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发表时间：
2015-11
影响因子：
8.1
通讯作者：
Wolfrum C
中科院分区：
文献类型：
--
作者：
Beaton N;Rudigier C;Moest H;Müller S;Mrosek N;Röder E;Rudofsky G;Rülicke T;Ukropec J;Ukropcova B;Augustin R;Neubauer H;Wolfrum C
未能正确处理胰岛素对葡萄糖的反应是一个严重的健康问题，发生在肥胖期间，并且与 2 型糖尿病的发展有关。含有葡萄糖转运蛋白 4 (GLUT4) 的囊泡易位和质膜融合促进了胰岛素刺激的葡萄糖摄取，这是餐后葡萄糖处理的限速步骤。我们分析了 Tusc5 在体外和体内调节胰岛素刺激的 Glut4 介导的葡萄糖摄取中的作用。此外，我们测量了两个患者队列中的 Tusc5 表达。在此，我们报告 TUSC5 在体外和体内控制脂肪细胞中胰岛素刺激的葡萄糖摄取。 TUSC5 在长时间的胰岛素刺激过程中促进 GLUT4 和其他关键运输蛋白的正确再循环，从而实现正确的蛋白质定位和完整的囊泡形成，最终实现胰岛素刺激的葡萄糖摄取。 Tusc5 敲除小鼠表现出葡萄糖处理受损，TUSC5 表达可预测肥胖个体的葡萄糖耐量，与体重无关。此外，我们发现 TUSC5 是 PPARγ 靶标，如果没有 TUSC5，TZD 的抗糖尿病作用会显着减弱。总的来说，这些发现将 TUSC5 确定为一种脂肪组织特异性蛋白，能够实现适当的蛋白质回收，将无处不在的囊泡运输机制与组织特异性胰岛素介导的脂肪组织中的葡萄糖摄取联系起来，并维持小鼠和人类的健康代谢表型。 Tusc5 通过调节 GSV 回收机制来调节脂肪组织中的葡萄糖摄取。 Tusc5 基因敲除小鼠由于脂肪组织葡萄糖摄取受损而出现胰岛素抵抗。罗格列酮部分通过诱导 Tusc5 改善葡萄糖稳态。 Tusc5 是一种新型脂肪特异性接头蛋白，将 Glut4 运输与普遍存在的机制连接起来。
Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted. Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans. Tusc5 regulates glucose uptake in adipose tissue by modulating the GSV recycling machinery. Tusc5 knockout mice develop insulin resistance due to impaired adipose tissue glucose uptake. Rosiglitazone improves glucose homeostasis in part through the induction of Tusc5. Tusc5 is a novel adipose specific adaptor protein linking Glut4 trafficking to the ubiquitous machinery.