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Macrophage IRX3 promotes diet-induced obesity and metabolic inflammation
Nature Immunology ( IF 27.7 ) Pub Date : 2021-09-23 , DOI: 10.1038/s41590-021-01023-y
Jingfei Yao 1 , Dongmei Wu 1, 2 , Chunyan Zhang 1 , Ting Yan 3 , Yiheng Zhao 1, 2, 4 , Hongyu Shen 1, 2, 4 , Kaili Xue 1 , Xun Huang 1, 2, 4 , Zihao Wang 1 , Yifu Qiu 1, 2
Affiliation  

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.



中文翻译:

巨噬细胞 IRX3 促进饮食诱导的肥胖和代谢炎症

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,人们对 IRX3 在哪些细胞中以及如何进行这种控制知之甚少。在这里,我们报告巨噬细胞 IRX3 促进代谢炎症以加速肥胖和 2 型糖尿病的发展。Irx3骨髓特异性缺失的小鼠通过增加适应性产热来保护免受饮食引起的肥胖和代谢疾病。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能信号传导,从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其泛素化来稳定 IRX3,从而增强 IRX3 的转录能力。总之,我们的研究结果确定了一个新的参与者,巨噬细胞 IRX3,它可以控制体重和代谢炎症,将 IRX3 作为治疗靶点。

更新日期:2021-09-23
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