TBC1D1 regulates insulin- and contraction-induced glucose transport in mouse skeletal muscle.
TBC1D1 regulates insulin- and contraction-induced glucose transport in mouse skeletal muscle.
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DOI：
10.2337/db09-1266
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发表时间：
2010-06
期刊：
影响因子：
7.7
通讯作者：
Goodyear LJ
中科院分区：
文献类型：
--
作者：
An D;Toyoda T;Taylor EB;Yu H;Fujii N;Hirshman MF;Goodyear LJ
TBC 1D 1是TBC 1 Rab-GT3蛋白家族的成员，在骨骼肌中高度表达。胰岛素和收缩增加磷酸化Akt底物基序（PAS）上的TBC 1D 1磷酸化，但TBC 1D 1在肌肉中的功能尚不清楚。遗传连锁分析显示，TBC 1D 1 R125 W错义变体可导致人类严重肥胖。本研究的目的是确定TBC 1D 1是否调节骨骼肌中的葡萄糖转运。在体内基因注射和电穿孔被用来过表达野生型和几个突变TBC 1D 1蛋白在小鼠胫骨前肌，葡萄糖转运在体内进行了测量。在TBC 1D 1 PAS磷酸化没有变化的情况下，肥胖相关的R125 W突变体的表达显著降低了胰岛素刺激的葡萄糖转运。在R125 W突变体中同时表达TBC 1D 1的无活性Rab-GTdR（GAP）结构域逆转了由R125 W突变体引起的葡萄糖转运减少。令人惊讶的是，在四个保守的Akt和/或AMP活化蛋白激酶预测的磷酸化位点（4P）上突变为Ala的TBC 1D 1的表达对胰岛素刺激的葡萄糖转运没有影响。相反，TBC 1D 1 4P突变体的表达降低了收缩刺激的葡萄糖转运，这一作用通过TBC 1D 1 Rab-GAP活性的同时破坏来防止。R125 W突变对收缩刺激的葡萄糖转运没有影响。TBC 1D 1调节胰岛素和收缩刺激的葡萄糖转运，这是通过不同的机制发生的。TBC 1D 1的R125 W突变损害骨骼肌葡萄糖转运，这可能是与该突变相关的肥胖的机制。
TBC1D1 is a member of the TBC1 Rab-GTPase family of proteins and is highly expressed in skeletal muscle. Insulin and contraction increase TBC1D1 phosphorylation on phospho-Akt substrate motifs (PASs), but the function of TBC1D1 in muscle is not known. Genetic linkage analyses show a TBC1D1 R125W missense variant confers risk for severe obesity in humans. The objective of this study was to determine whether TBC1D1 regulates glucose transport in skeletal muscle. In vivo gene injection and electroporation were used to overexpress wild-type and several mutant TBC1D1 proteins in mouse tibialis anterior muscles, and glucose transport was measured in vivo. Expression of the obesity-associated R125W mutant significantly decreased insulin-stimulated glucose transport in the absence of changes in TBC1D1 PAS phosphorylation. Simultaneous expression of an inactive Rab-GTPase (GAP) domain of TBC1D1 in the R125W mutant reversed this decrease in glucose transport caused by the R125W mutant. Surprisingly, expression of TBC1D1 mutated to Ala on four conserved Akt and/or AMP-activated protein kinase predicted phosphorylation sites (4P) had no effect on insulin-stimulated glucose transport. In contrast, expression of the TBC1D1 4P mutant decreased contraction-stimulated glucose transport, an effect prevented by concomitant disruption of TBC1D1 Rab-GAP activity. There was no effect of the R125W mutation on contraction-stimulated glucose transport. TBC1D1 regulates both insulin- and contraction-stimulated glucose transport, and this occurs via distinct mechanisms. The R125W mutation of TBC1D1 impairs skeletal muscle glucose transport, which could be a mechanism for the obesity associated with this mutation.
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影响因子：
7.7
作者：
Karlsson, HKR;Zierath, JR;Wallberg-Henriksson, H
通讯作者：
Wallberg-Henriksson, H
影响因子：
3.5
作者：
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通讯作者：
Shattuck, Donna
影响因子：
4.8
作者：
Chavez, Jose A.;Roach, William G.;Lienhard, Gustav E.
通讯作者：
Lienhard, Gustav E.
影响因子：
4.8
作者：
Kane, S;Sano, H;Lienhard, GE
通讯作者：
Lienhard, GE
影响因子：
3.5
作者：
LEE, AD;HANSEN, PA;HOLLOSZY, JO
通讯作者：
HOLLOSZY, JO