RNA结合蛋白QKI通过促进白色脂肪棕色样转化抑制胰岛素抵抗的发生发展及其分子机制

Obesity and its derived insulin resistance are a debilitating health problem in Chinese population. Improving the wellness of white fat tissue is helpful for weight loss and insulin signal sensitization. The recent findings disclosed that subcutaneous fat tissue is dynamic and reprogrammable, under certain conditions, brown-fat like cell is reformed leading to release of heat at costs of energy products, like glucose and lipids, such alterations facilitates with the homestasis of white fat tissue. During characterizations of QKI novel functions and mechanisms, we set up QKI knock-out mice in fat tissue. Our previous observations disclosed that QKI expression was enriched in the brown fat compared to the white ones. Under cold stimulus, QKI expression was highly intensified corresponding with the increase of beige fat in subcutaneous region. QKI loss in fat tissue showed a weak response in the amount of beige fat after cold treatment. These data strongly indicated that QKI is a novel regulator in the beige fat fate-decision. Combining with both in-vivo mice model and in-vitro cell one, we’ll further explore the altered metabolic parameters mediated by QKI and detect the molecular phenotype and relevant underlying critical regulatory mechanisms. In the high fat diet mice after deletion and gain of QKI in mice, the protective roles of QKI were consolidated from both positive and negative aspects. This study will provide a novel target for the deeply understanding and clarifications of obesity and insulin resistance.

肥胖及其引起的胰岛素抵抗是近年来威胁中国人群的重要疾病，改善白色脂肪组织的代谢状态有助于减肥和提高胰岛素敏感性。最新研究发现，皮下脂肪具有动态可塑性， 在一定条件下产生棕色样脂肪，大量消耗糖脂等能量物质，释放热量，保持白色脂肪组织的健康稳态。申请人一直从事RNA结合蛋白QKI的功能和机制探索，建立了QKI脂肪组织特异性敲除小鼠。前期研究发现，QKI在棕色脂肪组织中高表达；寒冷刺激下，随者皮下棕色样脂肪生成增多，QKI表达水平显著提高。敲除QKI的小鼠，棕色样脂肪组织的生成明显减少，高度提示QKI是一个新的决定棕色样（米色）脂肪的蛋白。本课题利用小鼠和细胞模型，研究QKI对寒冷条件下代谢功能指标的影响，检测棕色样脂肪分子表型变化，探索新的关键分子机制；在高脂饮食小鼠中，利用QKI缺失和转基因高表达小鼠，正反角度明确QKI对胰岛素抵抗的防护效应，全新认识并阐明肥胖和胰岛素抵抗防治的新靶点。

本课题主要针对RNA结合蛋白QKI 在白色脂肪细胞与棕色脂肪细胞的功能及其调控机制进行研究，特别是在肥胖以及寒冷的病理条件下，该分子调控的价值与意义。课题首次发现该蛋白在白色脂肪与棕色脂肪中均有表达，且在寒冷诱导条件下以及高脂肪喂养条件下均有增高，提示其参与脂肪细胞的能量代谢。在脂肪组织中特异性敲除该基因后，发现小鼠对寒冷刺激耐受性增高，表现出体温高，棕色脂肪生成增多，白色脂肪明显棕色化。全身代谢表型出现耗氧量增高；热量生成增多；CT检测脂肪含量明显减少。 进一步高脂肪喂养条件下，发现体重降低，糖耐量与胰岛素敏感性均提高。利用多种组学探讨分子机制，发现QKI增高作为负反馈刹车系统，通过影响RNA转运、翻译抑制等多个转录后步骤，对线粒体脂肪酸的氧化产生负性调控，其主要的靶基因是线粒体生成相关的pGC1a 和解偶联分子UCP1。此外AAV-ShRNA QKI 皮下脂肪中进行注射后，能够保护肥胖小鼠代谢表型。