GPSM1基因调节脂肪炎症反应致2型糖尿病的机制研究

Chronic low-degree inflammation of adipose tissue is a key factor of type 2 diabetes (T2D). Genome-wide association studies firstly identified GPSM1 was significantly associated with T2D. Previously, we have also found GPSM1 polymorphisms correlated with quantitative traits, such as insulin resistance and body fat content. However, the mechanism of GPSM1 regulating glucose and lipid metabolism remains largely unclear. Our previous study showed that expression of GPSM1 was upregulated in adipose tissue of mice feed with high fat diet. Immunohistochemical staining revealed that GPSM1 was located in macrophages around the adipocytes. Inducing macrophages transformation to M1 could stimulate expression of GPSM1 and silencing GPSM1 would inhibit chemotaxis of macrophages in vitro, suggesting that GPSM1 may play an important role in inflammatory process. On the base of these, this study will further adopt macrophage-specific GPSM1 knockout mice as well as cell lines to observe the effects of GPSM1 on inflammation and insulin resistance of adipose tissue, and elucidate the mechanism from chemokine signal transduction MEK/ERK pathway. Our research is of importance to know the pathogenesis, and will provide new insights into treatment of T2D with the development of the small molecule targeting on the inhibition of GPSM1.

慢性低度脂肪炎症是引起胰岛素抵抗导致2型糖尿病（T2D）发生的关键因素之一。本项目组前期参与的全基因组关联研究首次发现GPSM1基因与T2D发病显著相关，进一步筛查发现GPSM1编码区的多态性位点与胰岛素抵抗、体脂含量显著相关。但GPSM1调控糖脂代谢的分子机制不明。本项目组已发现GPSM1在高脂喂养小鼠脂肪组织中表达显著上调且主要分布于巨噬细胞等炎症细胞；体外诱导巨噬细胞向促炎M1型转化可上调GPSM1表达，而沉默GPSM1则可抑制巨噬细胞的趋化能力。因此本项目拟在此基础上，采用巨噬细胞特异性敲除GPSM1小鼠为模型，从分子、细胞、组织及动物层面研究GPSM1对脂肪炎症、胰岛素抵抗的影响，并从MEK/ERK相关通路探讨其调控趋化因子信号参与炎症细胞与脂肪细胞间对话的机制，以期为T2D发病机制的阐明和新治疗靶点的发现提供新思路。

人群全基因组关联研究发现GPSM1是2型糖尿病（T2D）的易感基因。我们前期在中国人群中（n = 10,939）发现，GPSM1的rs28445975位点可以显著增加中国人T2D的发病风险（OR = 1.115, P = 1.584×10-5）且和BMI显著相关（P = 6.783×10-3）。然而，GPSM1在哪种细胞并且如何发挥效应仍然未知。本项目研究发现，巨噬细胞的GPSM1可以促进代谢性炎症从而加速T2D和肥胖的发生发展。巨噬细胞特异性敲除GPSM1的小鼠可以通过抑制脂肪炎症，从而抵抗高脂饮食诱导的胰岛素抵抗、葡萄糖调节异常和肝脏脂肪变性。分子机制上，巨噬细胞GPSM1缺失可以通过Gnαi3/cAMP/PKA/CREB轴上调TNFAIP3转录，从而抑制TLR4诱导的NF-κB信号通路和促炎因子分泌。此外，与正常对照人群相比，超重或肥胖人群其腹内脂肪的GPSM1表达量显著增加，并且与临床代谢性状显著相关。综上所述，我们的研究阐明了T2D易感基因GPSM1通过调节巨噬细胞炎症反应引起胰岛素抵抗从而导致代谢性紊乱的分子机制。本研究的实施，进一步加深了对免疫细胞在代谢性疾病中作用的理解，以GPSM1为靶点可为T2D临床药物的开发提供新策略。

内容获取失败，请点击重试