奥氮平是治疗精神分裂症、双相障碍等精神疾病的一线药物，但长期使用可导致胰岛素抵抗，其机制迄今未明。研究表明，脂肪组织可分泌包含miRNA的外泌体到循环系统中，引起胰岛素抵抗。我们前期通过miRNA高通量测序发现奥氮平使脂肪组织miR-200c的表达显著增加，而miR-200c的靶基因IRS1参与胰岛素信号通路的调节，进一步发现血液中miR-200c含量增加，我们推测：奥氮平上调脂肪组织miR-200c的表达，升高的miR-200c以外泌体形式分泌至循环系统引起胰岛素抵抗。本项目将利用SD大鼠、3T3-L1细胞、L6大鼠成肌细胞等体内外实验模型，明确miR-200c在奥氮平诱发的胰岛素抵抗中的关键作用，阐明miR-200c通过外泌体途径分泌至循环系统并引起胰岛素抵抗的作用机制。本研究结果将从外泌体miRNA这个新视点揭示奥氮平诱发胰岛素抵抗的分子机制，为奥氮平代谢副作用的防治提供新思路。

Olanzapine has been widely used for the treatment of schizophrenia, bipolar disorder and other mental disorders. However, long-term use of olanzapine can lead to insulin resistance in patients, and the mechanism is still unclear. Studies have shown that adipose tissue can secrete exosomes containing microRNAs into circulation, causing insulin resistance in peripheral tissues. We previously found that olanzapine significantly increased the expression of microRNA-200c in adipose tissue by next-generation sequencing of microRNAs. The expression of microRNA-200c in the blood circulation was also increased. Moreover, insulin signaling pathway was inhibited. Therefore, we speculated that olanzapine up-regulated the expression of microRNA-200c in adipose tissue, and the increased microRNA-200c was secreted into circulation through exosomes, causing insulin resistance in other peripheral tissues. In this study, we will apply in vivo and in vitro experimental models of SD rats, 3T3-L1 cells, L6 rat myoblasts and primary rat hepatocytes to clarify the key role of microRNA-200c in olanzapine-induced insulin resistance, and elucidate the molecular mechanism of exsomal microRNA-200c in olanzapine induced insulin resistance. The results of this study will reveal the molecular mechanism of olanzapine-induced insulin resistance from the new perspective of exosomal microRNAs, and provide new ideas for the prevention and treatment of metabolic side effects of olanzapine.