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

两种rab - gtpase激活蛋白（RabGAPs） TBC1D1及其密切同源物TBC1D4 （AS160）是胰岛素和收缩介导的骨骼肌葡萄糖摄取和脂质代谢的重要调节因子。TBC1D1和TBC1D4基因的突变与人类和小鼠的肥胖、胰岛素抵抗和2型糖尿病有关。尽管有明显的餐后葡萄糖耐受不良，但在RabGAP的任何一种消耗时，全身血糖仅受到轻微影响，这可能是由于涉及同源家族成员的代偿机制。然而，双缺陷Tbc1d1/Tbc1d4 （D1/4KO）小鼠表现出明显的葡萄糖、胰岛素和AICAR（5-氨基咪唑-4-羧酰胺核糖核苷酸，AMPK活性刺激物）耐受性受损，运动表现和跑步耐力下降。一致地，D1/4KO小鼠的完整分离骨骼肌由于GLUT4葡萄糖转运蛋白的调节受损，表现出胰岛素，AICAR和收缩刺激的葡萄糖摄取强烈减少。出乎意料的是，D1/4KO小鼠在跑步机上进行慢性间歇训练，可以挽救糖耐量、运动表现和耐力的损伤，这有力地表明运动诱导的骨骼肌糖代谢和血糖控制的替代途径的存在。本研究旨在(i)研究慢性运动对全身血糖和骨骼肌能量代谢的TBC1D1/ Tbc1d4独立代谢影响的分子机制，以及（ii）利用新的TBC1D1和Tbc1d4组织特异性敲除模型，深入分析运动诱导胰岛素敏感性改善中的个体RabGAP功能。

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.