VSIG4诱导PDK2表达在改善胰岛素抵抗中的作用及机制研究

M1 (Mφ) macrophages promote insulin resistance (IR), inhibiting M1 polarization of Mφ can improve IR. VSIG4 specifically expressed on Mφ. The preliminary study found that VSIG4 deficient (VSIG4-/-) Mφ is susceptible to M1 polarization, VSIG4-/- mice are more susceptible to obesity and IR induced by high fat diet, suggesting the involvement of VSIG4 in IR. Further study showed that VSIG4 can promote dehydrogenase pyruvate kinase kinase 2 (PDK2) expression, leading to decreased production of mitochondrial reactive oxygen(mtROS) , suppressing polarization of Mφ, but the mechanism of upregulated expression of PDK2 induced by VSIG4 is unknown.In this study, we will uncover the role of PDK2 invovled in IR and explore the molecular mechanism of VSIG4 in regulating the expression of PDK2 by using TAP and Co-IP. Then, we will investigate the intervention effect of VSIG4 on IR using VSIG4 agonistic antibody in vivo. This study will clarify the molecular mechanism of M1 polarization of macrophages inhibited by VSIG4 for the first time, and provide a theoretical basis for the design of immunotherapy against IR based by VSIG4.

M1巨噬细胞（Mφ）促进胰岛素抵抗（IR），因此抑制Mφ的M1极化可改善IR。VSIG4是特异表达于Mφ表面的共抑制分子，前期研究发现，VSIG4表达缺失（VSIG4-/-）的Mφ易发生M1极化，VSIG4-/-小鼠更易发生高脂饮食诱导的肥胖及IR，提示VSIG4参与IR的发病。进一步研究表明，VSIG4可促进Mφ丙酮酸激酶脱氢酶激酶2（PDK2）表达使线粒体活性氧产物（mtROS）减少，抑制Mφ的M1极化，但VSIG4促PDK2表达的机制不明。本研究拟：利用PDK2 KO小鼠明确PDK2对IR的调节；使用TAP、Co-IP等技术探寻VSIG4调节PDK2表达的分子机制；在体给予VSIG4激动型抗体，探讨基于VSIG4信号对IR的干预效果。本研究将首次阐明VSIG4抑制巨噬细胞M1极化的分子机制，为设计基于VSIG4干预IR的免疫治疗提供理论依据。

M1巨噬细胞(Mφ)促进胰岛素抵抗(IR)，因此抑制Mφ的M1极化可改善IR。VSIG4 是特异表达于Mφ表面的共抑制分子，前期研究发现，VSIG4表达缺失(VSIG4-/-)的Mφ 易发生M1极化，VSIG4-/-小鼠更易发生高脂饮食诱导的肥胖及IR，提示VSIG4参与IR的发病。进一步研究表明，VSIG4可促进Mφ丙酮酸激酶脱氢酶激酶2(PDK2)表达使线粒体活 性氧产物(mtROS)减少，抑制Mφ的M1极化，但VSIG4促PDK2表达的机制不明。本研究发现VSIG4通过活化PI3K-Akt-STAT3信号轴上调PDK2的表达，从而促进PDH依赖的线粒体mtROS的释负调巨噬细胞的M1活化，研究首次阐明VSIG4抑制巨噬细胞M1极化的分子机制，为设计基于VSIG4干预IR的免疫治疗提供了理论依据。