肝细胞因子Sparcl1调控机体胰岛素敏感性的作用及机制研究

胰岛素抵抗是2型糖尿病与代谢综合征发病的重要基础，然而其产生机制尚不清楚。课题组前期工作首次发现一种新的细胞因子Sparcl1在高脂喂养和ob/ob小鼠肝脏中表达上调；腺病毒转染过表达Sparcl1，致小鼠胰岛素敏感性下降及血糖升高；机制研究表明，Sparcl1可激活JNK信号通路，抑制胰岛素下游关键信号AKT磷酸化，并上调糖异生关键酶表达。基于以上工作提出科学假设：Sparcl1可能通过激活JNK通路导致机体胰岛素抵抗发生。本项目拟开展:（1）采用腺病毒转染及基因敲除模型，明确Sparcl1对于外周组织胰岛素敏感性及胰岛素信号通路的调控作用；（2）体外及分子水平阐明Sparcl1调控胰岛素信号通路的机制；（3）人群队列中明确血清Sparcl1水平及基因型与代谢性疾病的关联性。从分子、细胞、动物及人群整体水平，全面揭示Sparcl1调控胰岛素抵抗的作用机制，并探讨作为疾病干预靶点的可能性。

Insulin resistance is the most powerful predictor of type 2 diabetes and metabolic syndrome, yet the molecular mechanism of insulin resistance remains elusive. Our previous work, using high-fat-diet-induced obese mice and ob/ob mice, discovered that a new hepatokine Sparcl1 was significantly increased in fatty livers. Hepatic overexpression of Sparcl1 resulted in decreased insulin sensitivity in C57BL/6 mice; further study demonstrated that overexpression of Sparcl1 activates the JNK signaling pathway, inhibits the phosphorylation of AKT, and up-regulates the expression of key gluconeogenesis enzymes. The above data indicated that Sparcl1 might trigger insulin resistance through activating the JNK pathway. Therefore, our project will further investigate: (1) the metabolic phenotype of liver and other peripheral tissues using Sparcl1 ShRNA and gene knockout model; (2) the molecular mechanism of Sparcl1 regulating insulin sensitivity; (3) the association between serum Sparcl1 levels and genotypes with insulin resistance and metabolic diseases in prospective cohort. This study will lead to a better understand of the pathogenesis of insulin resistance and Sparcl1 may also provide a promising target for the treatment of insulin resistance.