Mechanisms of exercise-induced improvements in whole-body glycemia in RabGAP-deficient mice

两个Rab-GTPase激活蛋白(RabGAPs)TBC1D1及其同源物TBC1D4(AS160)是胰岛素和收缩介导的骨骼肌葡萄糖摄取和脂肪代谢的重要调节因子。在人类和小鼠中，TBC1D1和TBC1D4基因的突变都与肥胖、胰岛素抵抗和2型糖尿病有关。尽管存在明显的餐后葡萄糖耐量异常，但耗尽任何一种RabGAP后，全身血糖只会受到轻微的影响，这可能是由于涉及同源家庭成员的代偿机制。然而，Tbc1d1/Tbc1D4(D1/4KO)双缺陷小鼠表现出显著的葡萄糖、胰岛素和AICAR(5-氨基咪唑-4-甲酰胺核苷酸，AMPK活性刺激物)耐力受损，以及运动能力和跑步耐力下降。由于GLUT4葡萄糖转运蛋白的调节受损，来自D1/4KO小鼠的完整的分离骨骼肌一直显示出胰岛素、AICAR和收缩刺激的葡萄糖摄取显著减少。出乎意料的是，在跑步机上对D1/4KO小鼠进行慢性间歇训练可以挽救葡萄糖耐量、运动能力和耐力方面的损害，强烈表明存在运动诱导的骨骼肌葡萄糖代谢和血糖控制的替代途径。本建议旨在(I)研究慢性运动对全身血糖和骨骼肌能量代谢的非依赖性代谢效应的分子机制，以及(Ii)利用针对TbC1d1和TBC1D4的新的组织特异性基因敲除模型，深入分析单个RabGAP在运动诱导的胰岛素敏感性改善中的作用。

The two Rab-GTPase-activating proteins (RabGAPs) TBC1D1 and its close homologue TBC1D4 (AS160) are important regulators of insulin- and contraction-mediated glucose uptake and lipid metabolism in skeletal muscle. Mutations in the genes for TBC1D1 and TBC1D4 have been associated with obesity, insulin resistance and type 2 diabetes in both humans and mice. Despite marked postprandial glucose intolerance, whole-body glycaemia is only mildly affected upon depletion of either RabGAP, presumably due to compensatory mechanisms involving the homologous family member. However, double-deficient Tbc1d1/Tbc1d4 (D1/4KO) mice show substantially impaired glucose, insulin and AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide, stimulator of AMPK activity) tolerance as well as reduced exercise performance and running endurance. Consistently, intact isolated skeletal muscle from D1/4KO mice displayed strongly reduced insulin-, AICAR- and contraction-stimulated glucose uptake due to impaired regulation of GLUT4 glucose transporters. Unexpectedly, chronic interval training of D1/4KO mice on treadmills rescues the impairment in glucose tolerance, exercise performance and endurance, strongly indicating the presence of exercise-induced alternative pathways for skeletal muscle glucose metabolism and glycemic control. The present proposal aims at (i) investigating the molecular mechanism underlying the observed TBC1D1/TBC1D4-independent metabolic effects of chronic exercise on whole-body glycemia and skeletal muscle energy metabolism, and (ii) performing an in-depth analysis of individual RabGAP function in exercise-induced improvements of insulin sensitivity using novel tissue-specific knockout models for the Tbc1d1 and Tbc1d4.