Tim-4通过LKB1调控巨噬细胞线粒体稳态参与肥胖的作用研究

肥胖是慢性低度炎症的病理状态。脂肪组织巨噬细胞（ATMs）是代谢炎症及肥胖发生的关键因素，线粒体代谢可重塑ATMs并控制肥胖进程。免疫调节分子Tim-4高表达于巨噬细胞，参与多种免疫性疾病，申请者前期发现肥胖小鼠ATMs表达Tim-4升高，但Tim-4在巨噬细胞代谢重编程及肥胖中的作用未见报道。近期发现巨噬细胞敲除Tim-4加重高脂诱导的肥胖，RNA-Seq等显示Tim-4敲除使巨噬细胞线粒体基因表达降低及功能受损，促进巨噬细胞向M1极化，质谱提示Tim-4与LKB1结合，干预该通路影响Tim-4对巨噬细胞的调节，进而提出Tim-4经LKB1调控线粒体重塑巨噬细胞参与肥胖的假说。本研究拟利用Tim-4及LKB1敲除等多种工具小鼠，系统研究Tim-4与LKB1互作调控巨噬细胞的机制及在肥胖中的作用。研究的开展有望解析ATMs稳态的调控机制，揭示Tim-4新型生物学功能，为肥胖干预提供新靶点。

Obesity is a serious health problem characterized by execessive expansion of the white adipose tissue coupled with a state of chronic, low-grade inflammation. Obesity-associated inflammation occurs as a result of immune cell infiltration, especially macrophage recruitment and activation in the adipose tissue and increased production of pro-inflammatory cytokines. Adipose tissue macrophages (ATMs) are responsible for obesity metabolic inflammation and insulin resistance. Mitochondrial metabolism reprograms ATMs and determines obesity consequences. Immunoregulator Tim-4 is selectively highly expressed on macrophages and involves in multiple immune diseases. We have found that obesity microenvironments induce Tim-4 expression on ATMs. However, the role of Tim-4 in metabolic reprogramming of macrophages and obesity remains unclear. Recently, we found that specific Tim-4 knockout in macrophages aggravated obesity induced by high fat diet. RNA-sequence, flow cytometry and qPCR assays showed that Tim-4 knockout led to decreased expression of mitochondrial genes and mitochondrial dysfunction, as well as M1 polarization of macrophages. Mass spectrometry,Co-IP and confocal imaging assays inidicated that Tim-4 interacted with LKB1. Intervention of LKB1 pathway affected Tim-4 mediated regulation on macrophages. Based on these data, we put forward the hypothesis that Tim-4 involves in obesity through regulating mitochondrial homeostasis and reprogramming macrophages via LKB1. In this study, Tim-4 and LKB1 conditional knockout mice and other tools would be used to investigate the key role of Tim-4 and LKB1 crosstalk in modulating macrophages and obesity. The accomplishment of this proposal is expected to clarify the regulatory mechanism of ATMs homeostasis, reveal the novel biological function of Tim-4 and provide the new candidate target for obesity intervention.