基于mTORC1/SREBP通路对白色/棕色脂肪的表型调控研究健脾调肝饮治疗肥胖的作用机制

Although the pathogenesis of simple obesity has not been fully elucidated, an increasing numbers of studies have confirmed that the energy imbalance of white/brown adipose tissue(WAT/BAT) is the primary cause of simple obesity. The mTORC1 signaling pathway, as an important part for energy regulation, participates in WAT/BAT phenotype transformation and regulates the downstream transcription factor SREBP which affects the occurrence and development of obesity. Given that the close relationship between the "disease cause by extract and turbid" theory and WAT/BAT, and the preliminary research on the treatment of obesity with JianPiTiaoGanYin(JPTGY) by promoting WAT browning, we hypothesize that "JPTGY could restore the internal environment homeostasis by promoting WAT browning through the mTORC1/SREBP signaling pathway." To validate it, the study is designed to testify the effect of mTOR pathway on WAT/BAT phenotype transformation in vivo and in vitro with lentivirus transfection and TALEN method, aiming to explore the molecular mechanism of energy balance regulated by JPTGY. From a new perspective - WAT/BAT，the molecular mechanism of obesity will be explained. This study will provide the scientific basis for future mechanistic studies and for designing obesity prevention strategies with Traditional Chinese Medicine.

白色/棕色脂肪介导的能量平衡稳态逐渐成为单纯性肥胖症的研究热点。mTORC1作为脂肪能量感受机制的中心，可通过感知能量变化并调控下游转录因子SREBP参与白色/棕色脂肪表型转化进而影响肥胖的发生发展。结合中医“膏浊致病”理论与肥胖的密切关系及前期研究证实健脾调肝饮可通过促进白色脂肪棕色化增加能量代谢治疗肥胖，我们提出“健脾调肝饮通过mTORC1/SREBP通路促进白色脂肪棕色化进而恢复能量稳态以达到减重目的”的假说。为此，本课题将从白色/棕色脂肪与能量代谢关系的角度出发，通过体内外实验阐明mTOR通路对白色/棕色脂肪表型的调控，并通过应用慢病毒转染、下游靶标特异性敲除等技术方法解析健脾调肝饮对mTOR通路的影响以探索其在肥胖治疗中脂肪能量代谢的调控方式及分子机制，以期从白色/棕色脂肪这一全新角度阐释肥胖的发生发展及膏浊理论的科学内涵，此研究将为肥胖的机制研究及中医防治策略提供新的理论依据。

白色/棕色脂肪介导的能量平衡稳态逐渐成为单纯性肥胖症的研究热点。前期研究证实以“膏浊致病”理论指导，以“健脾调肝化浊”为治则的健脾调肝饮可通过促进白色脂肪棕色化增加能量代谢治疗肥胖，但其具体作用机制尚未阐明。本课题围绕mTORC1作为脂肪能量感受机制的中心可通过感知能量变化并调控下游转录因子SREBP参与白色/棕色脂肪表型转化这一重要前提，依托单纯性肥胖症小鼠、3T3-L1脂肪细胞，通过体内外实验探究mTOR通路对白色/棕色脂肪表型的调控，并通过应用慢病毒转染、si-RNA等技术方法深入解析健脾调肝饮对mTOR通路的影响以探索其在肥胖治疗中脂肪能量代谢的调控方式及分子机制。研究结果表明白色/棕色脂肪表型转化贯穿肥胖发生、发展的始终，其发生、发展的过程与中医“膏浊致病”理论极为相似；健脾调肝饮可通过mTORC1/SREBP通路促进白色脂肪棕色化进而恢复能量稳态最终达到改善糖脂代谢、提高基础代谢率、减轻体重的目的，本研究从白色/棕色脂肪这一全新角度阐释肥胖的发生发展及膏浊理论的科学内涵，本研究为肥胖的机制研究及中医防治策略提供新的理论依据及重要靶点。