FKBP51通过UCP1增强肝脏线粒体功能在抵抗高脂诱导肥胖的机制研究

High fat diet would induce the changes in mice hepatic mitochondria, including content reduction, structure breaking, and dysfunction. Previously we discovered FKBP51 KO mice have higher energy expenditure and mitochondria oxidation than wild type (WT) mice according to serials analyses, including metabolism cages system, PET-CT and XF Extracellular Flux Analyzers. Furthermore, a high expression of UCP1 in FKBP51 KO mice liver was detected. To understand the role of FKBP51 in regulation of UCP1 and mitochondrial function, three study aims will proposed here. Frist, the mechanism of FKBP51 on UCP1 transcription and expression will be investigated. Second, the mechanism of FKBP51 KO on mitochondrial enhancement will be investigated by comparing the difference (mitochondrial content, structure, and function) of hepatic mitochondria in WT and FKBP51 KO mice fed with high fat diet, using electron microscope, real-time PCR, western blotting and a two-channel titration injection respirometer. Third, the role of UCP1 in above progress will also be observed. Completion of this work will increase our knowledge to the role of FKBP51 in regulation of UCP1 and mitochondrial function, and also will provide a clue of FKBP51 in the development of obesity.

高脂饮食将导致小鼠肝脏组织中线粒体含量减少、结构完整性破坏和功能障碍。我们前期通过小鼠代谢笼、PET-CT和细胞能量代谢分析仪发现FKBP51敲除小鼠呼吸代谢和线粒体氧化呼吸能力较野生型对照组明显增强；我们还发现FKBP51敲除小鼠肝脏中UCP1表达明显增高。在本项目中，将首先探讨敲除FKBP51对UCP1转录和表达的机制；其次，利用电镜、real-time PCR、western blotting和高分辨率线粒体呼吸测定仪，全面系统的分析高脂喂养的野生型和FKBP51敲除小鼠肝脏线粒体含量、结构和功能的差异，找出FKBP51 KO小鼠肝脏线粒体活性增强的分子机制，以及UCP1在此过程中介导的作用。通过本项目，将明确FKBP51影响UCP1表达以及对线粒体功能的相关调节机制，为系统阐述FKBP51与肥胖发生提供进一步的理论依据。

FKBP51可与糖皮质激素受体(GR)结合形成复合体，负反馈调节下丘脑-垂体-肾上腺轴的功能，对神经功能和机体代谢都有重要功能。高脂饮食将导致小鼠肝脏组织中线粒体含量减少、结构完整性破坏和功能障碍。本项目利用FKBP51基因敲除小鼠和其来源的MEF细胞，从整体、细胞和分子水平，阐明FKBP51通过调节Parkin的蛋白稳定性和线粒体自噬，参与肥胖中肝脏线粒体功能的调节，为治疗脂肪肝和肥胖提供了理论依据和治疗靶点。本项目还利用FKBP51基因敲除小鼠，通过小鼠行为学、电生理学和分子机制的研究，揭示FKBP51通过调节神经可塑性参与精神疾病的发生和发展。