上海交通大学医学院沈蕾研究团队在研究中取得进展。他们的论文发现了代谢调节因子LKB1控制脂肪组织ILC2 PD-1表达和线粒体稳态以预防胰岛素抵抗。这一研究成果于2024年5月20日发表在国际顶尖学术期刊《免疫》上。

据介绍，脂肪组织2型先天淋巴样细胞(ILC2s)通过维持2型免疫和促进脂肪转化来帮助维持代谢稳态。尽管2型先天淋巴样细胞隔室的损伤有助于肥胖相关的胰岛素抵抗，但其潜在机制尚未阐明。

该研究组发现肥胖小鼠和人类的2型先天淋巴样细胞表现出肝激酶B1 (LKB1)激活受损。LKB1基因缺失破坏2型先天淋巴样细胞线粒体代谢并抑制2型先天淋巴样细胞反应，导致胰岛素抵抗加剧。

从机制上讲，LKB1缺失通过激活NFAT诱导PD-1异常表达，NFAT通过抑制Bcl-xL表达而增强有丝分裂。阻断PD-1可恢复小鼠2型先天淋巴样细胞的正常功能，逆转肥胖诱导的胰岛素抵抗。总的来说，这些数据表明LKB1-PD-1轴是治疗代谢性疾病的有希望的治疗靶点。

附：英文原文

Title: Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance

Author: Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G. Engleman, Lei Shen

Issue&Volume: 2024-05-20

Abstract: Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasisby sustaining type 2 immunity and promoting adipose beiging. Although impairment ofthe ILC2 compartment contributes to obesity-associated insulin resistance, the underlyingmechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humansexhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disruptedILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbatedinsulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expressionthrough activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xLexpression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-inducedinsulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis asa promising therapeutic target for the treatment of metabolic disease.

DOI: 10.1016/j.immuni.2024.04.024

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00229-2