近日，华中科技大学王从义等研究人员合作发现，PDIA3定义出一类新的脂肪组织巨噬细胞亚群可加剧肥胖和代谢紊乱的发展。2024年9月17日，《细胞—代谢》杂志在线发表了这项成果。

研究人员进行了单核RNA测序（snRNA-seq），揭示了一种独特的失调性脂肪组织巨噬细胞（ATM）亚群，被定义为ATF4^hi PDIA3^hi ACSL4^hi CCL2^hi的炎性和代谢激活巨噬细胞（iMAM），其中PDIA3对于维持其迁移和促炎特性是必需的。

在机制上，ATF4作为代谢应激感应器转录PDIA3，后者通过RhoA-YAP信号通路对RhoA活性进行氧化还原控制，增强iMAM的促炎和迁移特性。通过递送Pdia3小干扰RNA（siRNA）的脂质体有效抑制了脂肪炎症和高脂饮食（HFD）诱导的肥胖。这些数据表明，针对PDIA3表达或活性抑制iMAM的策略，可能是对抗肥胖和代谢紊乱的临床可行方法。

据介绍，ATM在维持脂肪组织稳态和调控代谢炎症中发挥重要作用。由于ATM具有广泛的功能异质性和表型可塑性，识别肥胖环境下真正致病的ATM亚群是必要的。

附：英文原文

Title: PDIA3 defines a novel subset of adipose macrophages to exacerbate the development of obesity and metabolic disorders

Author: Jia-Hui Luo, Fa-Xi Wang, Jia-Wei Zhao, Chun-Liang Yang, Shan-Jie Rong, Wan-Ying Lu, Qi-Jie Chen, Qing Zhou, Jun Xiao, Ya-Nan Wang, Xi Luo, Yang Li, Dan-Ni Song, Cai Chen, Cheng-Liang Zhang, Su-Hua Chen, Ping Yang, Fei Xiong, Qi-Lin Yu, Shu Zhang, Shi-Wei Liu, Fei Sun, Cong-Yi Wang

Issue&Volume: 2024-09-17

Abstract: Adipose tissue macrophages (ATMs) play important roles in maintaining adipose tissue homeostasis and orchestrating metabolic inflammation. Given the extensive functional heterogeneity and phenotypic plasticity of ATMs, identification of the authentically pathogenic ATM subpopulation under obese setting is thus necessitated. Herein, we performed single-nucleus RNA sequencing (snRNA-seq) and unraveled a unique maladaptive ATM subpopulation defined as ATF4hiPDIA3hiACSL4hiCCL2hi inflammatory and metabolically activated macrophages (iMAMs), in which PDIA3 is required for the maintenance of their migratory and pro-inflammatory properties. Mechanistically, ATF4 serves as a metabolic stress sensor to transcribe PDIA3, which then imposes a redox control on RhoA activity and strengthens the pro-inflammatory and migratory properties of iMAMs through RhoA-YAP signaling. Administration of Pdia3 small interfering RNA (siRNA)-loaded liposomes effectively repressed adipose inflammation and high-fat diet (HFD)-induced obesity. Together, our data support that strategies aimed at targeting iMAMs by suppressing PDIA3 expression or activity could be a viable approach against obesity and metabolic disorders in clinical settings.

DOI: 10.1016/j.cmet.2024.08.009

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00361-9