北京大学未来技术学院分子医学研究所邱义福团队的最新研究发现，巨噬细IRX3参与调控饮食诱导的肥胖和代谢性炎症。2021年9月23日，国际学术期刊《自然—免疫学》发表了这一成果。

研究人员发现巨噬细胞IRX3促进代谢炎症以加速肥胖和2型糖尿病的发展。通过增加适应性产热作用，具有Irx3髓样特异性缺失的小鼠可免受饮食诱导的肥胖和代谢疾病的侵害。从机制上讲，巨噬细胞IRX3促进促炎细胞因子转录，从而抑制脂肪细胞肾上腺素信号，进而抑制脂肪分解和产热。JNK1/2磷酸化IRX3，导致其二聚化和核转位以进行转录。

此外，脂多糖刺激通过抑制泛素化来稳定 IRX3，从而增强IRX3的转录能力。总之，该发现确定了巨噬细胞IRX3是调节体重和代谢炎症的重要因子，表明IRX3具有作为治疗靶点的潜力。

据介绍，代谢性炎症与肥胖密切相关，并与代谢性疾病的发病机制有关。FTO与多基因肥胖具有最强的遗传关联，IRX3介导FTO对体重的影响。然而，对哪些细胞以及IRX3如何实现这种控制的机制知之甚少。

附：英文原文

Title: Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation

Author: Yao, Jingfei, Wu, Dongmei, Zhang, Chunyan, Yan, Ting, Zhao, Yiheng, Shen, Hongyu, Xue, Kaili, Huang, Xun, Wang, Zihao, Qiu, Yifu

Issue&Volume: 2021-09-23

Abstract: Metabolic inflammation is closely linked to obesity, and is implicated in the pathogenesis of metabolic diseases. FTO harbors the strongest genetic association with polygenic obesity, and IRX3 mediates the effects of FTO on body weight. However, in what cells and how IRX3 carries out this control are poorly understood. Here we report that macrophage IRX3 promotes metabolic inflammation to accelerate the development of obesity and type 2 diabetes. Mice with myeloid-specific deletion of Irx3 were protected against diet-induced obesity and metabolic diseases via increasing adaptive thermogenesis. Mechanistically, macrophage IRX3 promoted proinflammatory cytokine transcription and thus repressed adipocyte adrenergic signaling, thereby inhibiting lipolysis and thermogenesis. JNK1/2 phosphorylated IRX3, leading to its dimerization and nuclear translocation for transcription. Further, lipopolysaccharide stimulation stabilized IRX3 by inhibiting its ubiquitination, which amplified the transcriptional capacity of IRX3. Together, our findings identify a new player, macrophage IRX3, in the control of body weight and metabolic inflammation, implicating IRX3 as a therapeutic target.

DOI: 10.1038/s41590-021-01023-y

Source: https://www.nature.com/articles/s41590-021-01023-y