LIGHT（TNFSF14）抑制米黄色脂肪形成调控肥胖发生的机制研究

Obesity and its complications have affected a signifcant part of the population worldwide for several decades. It is the excessive accumulation of energy sources in body giving rise to hypertrophy or hyperplasia of adipocyte which finally leads to obesity. Researches proved that there are two mainly kinds of adipocytes in fat named white adipocyte which stores energy and induces obesity and another called beige adipocyte which transforms energy to heat and reduces the fat. Epidemiological data shows that LIGHT (Lymphotoxin-like Inducible protein that competes with Glycoprotein D for Herpes virus entry on T cells) overexpressed in obesity groups and its concentration in blood was positively related to Body Mass Index but some studys found the conflicting result that LIGHT inhibited formation of white adipocyte from the precursor. Based on this contradiction, we did some researches on beige adipocyte. Intrestingly, LIGHT could inhibit the differentiation of preadipocytes to beige adipocyte also which could explain why overexpression of LIGHT detected in obesity. Therefore, the current project is designed to investigate the mechanism of LIGHT inhibiting beige adipocyte formation. The whole project includes two main parts: Confirmation of receptor of LIGHT functioning in preadipocytes differentiation and identifaction of downstream elements in this pathway. The implementation of this project will not only help to elucidate the mechanism of obesity, but also find out some new ways or drug targets to the prevention or treatment of obesity.

肥胖已成为威胁人类健康的重要疾病。肥胖的发生与白色脂肪组织积累密切相关。白色脂肪组织主要由两种细胞组成：促进肥胖发生的白色脂肪细胞和抑制肥胖的米黄色脂肪细胞。流行病学统计显示肥胖人群LIGHT表达量高于瘦人群体，且含量与体重指数呈正相关。而细胞水平研究证明LIGHT能抑制脂肪前体细胞向白色脂肪细胞分化，提示LIGHT能抑制肥胖，这就形成了较大的矛盾。以此矛盾为切入点，前期预实验证明LIGHT不仅能抑制脂肪前体细胞向白色脂肪细胞分化，更重要的是LIGHT还可以抑制脂肪前体细胞向米黄色脂肪细胞分化，而米黄色脂肪细胞恰恰可以抑制肥胖发生，这就可以很好地解释以上矛盾了。本项目拟以LIGHT抑制米黄色脂肪形成为出发点，探讨LIGHT抑制米黄色脂肪形成的分子机制，确定LIGHT调控脂肪前体细胞向米黄色脂肪细胞分化所需要的受体，鉴定下游相互作用蛋白，确定其中的关键信号通路，以期为肥胖的防治提供新思路。

免疫系统在调节肥胖中的作用已越来越被人们所认识，LIGHT，又称TNFSF14作为免疫系统中重要细胞因子，其在肥胖中的作用及可能的机理目前并没有深入地了解。流行病学统计表明肥胖人群LIGHT表达量高于瘦人群体，且其含量与体重指数呈正相关。本研究前期结果显示高脂饮食诱导的肥胖小鼠皮下脂肪组织中LIGHT的表达量明显高于正常饮食小鼠，提示LIGHT可能对肥胖具有调控作用。深入探究证明，LIGHT能够抑制脂肪前体细胞向米黄色和白色脂肪细胞分化。LIGHT受体LTβR（淋巴毒素β受体）在脂肪组织中高表达，LTβR的活化强烈抑制脂肪前体细胞向米黄色和白色脂肪细胞分化，且脂肪组织特异性敲除LTβR一定程度上促进米黄色脂肪形成，表明LIGHT通过激活受体LTβR调控脂肪细胞分化。进一步研究表明LIGHT-LTβR分别能够抑制米黄色脂肪细胞形成过程中JNK的磷酸化和白色脂肪细胞形成过程中p65的磷酸化，利用JNK和NFκB信号通路抑制剂能分别抑制米黄色和白色脂肪细胞形成，说明LIGHT-LTβR可通过JNK和NFκB信号通路分别抑制米黄色和白色脂肪细胞形成。近期结果显示LIGHT可抑制脂肪细胞分化初期葡萄糖转运蛋白Glut4的表达，降低分化过程中葡萄糖的吸收和利用，而肥胖模型中LIGHTko小鼠脂肪组织中Glut4表达上调，推测LIGHT可能通过抑制脂肪细胞形成初期葡萄糖转运蛋白Glut4的表达，从而抑制脂肪细胞葡萄糖吸收，进而抑制成熟脂肪细胞形成，该部分有待深入探讨。本课题的研究能够加深人们对免疫系统，特别是免疫分子调控肥胖及机体代谢的认识，LIGHT能够显著抑制成熟脂肪细胞的形成，这为肥胖及相关代谢疾病的预防和治疗提供了新的理论依据。