基于米色脂肪分化中mTOR-STAT3-Notch信号调控探讨奥氮平诱导胰岛素抵抗的机制

项目名称： 基于米色脂肪分化中mTOR-STAT3-Notch信号调控探讨奥氮平诱导胰岛素抵抗的机制

项目编号： No.81503121

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张学丽

作者单位： 东南大学

项目金额： 17.9万元

中文摘要： 奥氮平（OLA）诱导的胰岛素抵抗和代谢紊乱可显著增加糖尿病、心血管疾病风险。目前从中枢作用出发的相关研究仅能解释OLA导致的早期摄食与体重增加，无法回答OLA代谢风险的关键机制。近年研究发现，米色脂肪功能失调与胰岛素抵抗、糖脂代谢异常等病理过程密切相关。申请人预实验结果证实：OLA可明显抑制米色脂肪细胞的分化及功能活化，并上调mTOR、Notch信号。基于以上事实，本项目拟综合运用分子生物学、活体荧光成像、化学干预和基因沉默方法，系统性研究米色脂肪功能失调与OLA致胰岛素抵抗的关联、OLA致米色脂肪功能失调的分子机制以及mTOR-Notch通路化学干预对OLA相关胰岛素抵抗的改善作用，以期从能量代谢关键分子、脂肪细胞和整体动物水平探讨OLA诱导胰岛素抵抗的外周作用机制。本项目对深入解析OLA的代谢风险具有重要意义，并可为临床干预策略的创新提供科学依据。

中文关键词： 奥氮平；米色脂肪；胰岛素抵抗；mTOR-STAT3-Notch；信号通路；代谢风险

英文摘要： Olanzapine (OLA) induced insulin resistance and metabolic disorder could dramatically increase the risk of cardiovascular disease and diabetes mellitus. Research based on the central actions of OLA could only explain the increase of food intake and weight gain, but the key mechanism for OLA associated metabolic risks remains unanswered. Beige fat plays an important role in energy balance and its dysfunction is tightly associated with insulin resistance and glycolipid metabolic disturbance. We found that OLA could inhibit the differentiation and functioning of beige adipocytes and up-regulate the mTOR-Notch signal pathway thereof in our preliminary experiment. In our research, we aim to focus on the mTOR-STAT3-Notch signaling in the differentiation of beige fat and make a combinatory use of molecular biology, in vivo fluorescence imaging and chemical intervention techniques to uncover the relationship between beige fat dysfunction and OLA-induced insulin resistance, the mechanism of OLA-induced beige fat dysfunction and the outcome of chemical intervention to OLA-induced insulin resistance, across the level of energy metabolism-associated molecules, adipocytes and animal. Our study is expected to provide novel insights into the metabolic risks of OLA, and give rationale scientific basis for innovative intervention strategies in the clinic.

英文关键词： Olanzapine;beige fat;Insulin resistant;mTOR-STAT3-Notch pathway;Metabolic risk