米色脂肪通过分泌miR-338改善肝脏和骨骼肌胰岛素抵抗的机制研究

胰岛素抵抗是促进Ⅱ型糖尿病发生发展的核心因素。以往经典研究多集中于各个组织内部调控的分子机制，但近期研究表明，组织器官间通讯在机体代谢稳态中发挥了重要作用，因此寻找介导组织器官对话的关键信号分子，对治疗胰岛素抵抗具有重大创新意义。激活米色脂肪可以显著改善高脂诱导的胰岛素抵抗，但其调节全身血糖稳态的机制尚不明确。申请人研究发现米色脂肪分泌的miR-338能够作为特异性代谢信号分子，介导米色脂肪与肝脏/骨骼肌之间的通讯与调控作用，由此改善全身胰岛素抵抗。本项目拟利用CRISPR-Cas9系统构建miR-338敲除/敲入小鼠，通过生物信息学方法计算筛选以及皮下脂肪移植技术，从分泌机制和靶组织调控两方面，深入研究分泌miR-338介导的米色脂肪--肝脏/骨骼肌之间的调控作用。从组织器官间相互调控的角度阐明通过激活米色脂肪改善全身胰岛素抵抗的分子机制，为临床治疗提供新的信号分子和治疗策略。

Insulin resistance plays a pivotal role in Type-II diabetes occurrence and development. Recent studies have shown that the inter-organ crosstalk is very important for whole body metabolism homeostasis. Thus, locating key signal molecular which mediates crosstalk could be an innovative approach for curing insulin resistance. It is known that activation of beige adipose tissue can effectively ameliorate high-fat induced insulin resistance. Yet, the mechanism of how beige adipose can regulate whole body glucose homeostasis remains unclear. In our preliminary study, we found that miR-338, which is secreted by beige adipose, can ameliorate insulin resistance by mediating the communication between beige adipose and liver/muscle as a specific signal transduction molecular. In this proposal, using bioinformatics algorithms and CRISPR-Cas9 based miR-338 knock-out technique, we plan to study the regulatory mechanism in time and space between beige adipocyte and liver/muscle mediated by exosomal-derived miR-338 from the aspect of secreting mechanism and target tissue regulation. We plan to elucidate the molecular mechanism of how beige fat activation ameliorates whole body insulin resistance from the angle of tissue crosstalk. Successful completion of this study will provide new signal transduction molecular as target for future clinical therapy.