GLUT1在棕色脂肪介导的适应性产热及葡萄糖代谢过程中的作用和机制

Obesity has become a global pandemic. The imbalance between energy storage and expenditure is the major cause for the development of obesity. Brown adipose tissue (BAT) has been reported to prevent obesity by dissipating excessive energy in the form of heat through the actions of uncoupling protein 1 (UCP1) located in mitochondria. Cold conditions and β3-adrenergic receptor agonists effectively up-regulate and activate the thermogenic machinery in BAT and promote glucose uptake and utilization, thereby restoring energy homeostasis. The activation of BAT by cold challenge has been shown to reduce body weight in both humans and animals. However, although activation of BAT was consistently shown to be associated with elevated expression of FGF21 and the glucose transporter1 (GLUT1), the role of GLUT1 in BAT function remains elusive. In addition, the biological relevance of massively elevated glucose uptake in BAT during adaptive thermogenesis was poorly understood. The present study will (1) elucidate how cold challenge, via activation of sympathetic nerve system, induce GLUT1 expression in BAT at both transcriptional and post-translational levels; (2) employ adipocyte-selective GLUT1 knockout mouse model as well as in vitro approaches to investigate the functional role of GLUT1 in BAT-mediated adaptive thermogenesis and whole body glucose clearance. These findings from this study will contribute to the current understanding of BAT in whole-body metabolism, as well as any inter-organ crosstalk for maintaining energy and glucose homeostasis.

肥胖症已经成为影响人类健康的重要问题。机体能量储存与消耗失衡是导致肥胖的直接原因，而棕色脂肪组织可以通过产热的方式将体内过多的能量释放出来。寒冷的条件和ß3受体激动剂可以有效激活棕色脂肪，促进其对葡萄糖的吸收。在棕色脂肪激活的过程中往往伴随着FGF21和葡萄糖转运体GLUT1表达的上升，但GLUT1表达调控的机理以及GLUT1在寒冷刺激下棕色脂肪摄取葡萄糖中发挥的作用和对棕色脂肪适应性产热有怎样的影响目前还不清楚。本研究将通过体内和体外实验，探索寒冷条件下GLUT1在棕色脂肪中表达的转录与翻译后调控机制，并利用脂肪细胞特异性敲除GLUT1小鼠揭示寒冷条件下GLUT1在棕色脂肪的葡萄糖摄入中发挥的作用，以及摄入的葡萄糖对棕色脂肪产热作用和全身葡萄糖的清除的生理意义。本课题的结果将全面揭示GLUT1在棕色脂肪中的调控机制、功能以及生理意义，为深入了解棕色脂肪在代谢中的地位提供新的理论依据。

棕色脂肪组织是人体维持体温的重要器官，可以通过颤抖性产热消耗掉体内高达75%的葡萄糖。棕色脂肪组织被认为具有对抗肥胖的潜力。因此，阐明由棕色脂肪摄入的葡萄糖在其非颤抖性过程中的机理和功能具有重要意义。尽管已经有研究发现，棕色脂肪中的GLUT1在寒冷刺激后表达会增加，而其功能和意义尚不明了。在我们的研究结果发现：1.β3肾上腺素受体的激活可以由mTOR信号通路介导GLUT1在棕色脂肪细胞中的表达；2. 利用腹腔注射GLUT1活性抑制剂STF31的野生小鼠和产生的GLUT1脂肪组织特异性敲除小鼠两个模型，通过直接的寒冷刺激或者β3肾上腺素受体激动剂诱导，从体内和体外两个层面证明了GLUT1参与了寒冷刺激下棕色脂肪内葡萄糖的转运过程；3. 寒冷刺激下由GLUT1介导的葡萄糖摄入只为短期产热提供部分能量，但对长期的适应性产热没有影响；4. 通过对高脂饲料喂养在GLUT1基因敲除小鼠中建立肥胖模型进行研究，揭示了GLUT1并不是介导棕色脂肪对全身葡萄糖清除的主要因子。本课题的结果全面揭示GLUT1在棕色脂肪中的调控机制、功能以及生理意义，为深入了解棕色脂肪在代谢中的地位提供新的理论依据。