Adipose progenitor cell-derived extracellular vesicles suppress macrophage M1 program to alleviate midlife obesity

Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu (), Yanjun Liu () and Cong-Yi Wang ()
Additional contact information
Qing Zhou: Huazhong University of Science and Technology
Jia Gao: Huazhong University of Science and Technology
Guorao Wu: Huazhong University of Science and Technology
Chenwei Wang: Baylor College of Medicine
Yan Yang: Huazhong University of Science and Technology
Teng Huang: Huazhong University of Science and Technology
Yi Wang: Huazhong University of Science and Technology
Tiantian Yue: Huazhong University of Science and Technology
Zhichao Gao: Huazhong University of Science and Technology
Hao Xie: Huazhong University of Science and Technology
Fei Xiong: Huazhong University of Science and Technology
Ke Xiang: Huazhong University of Science and Technology
Tuying Yong: Huazhong University of Science and Technology
Wanguang Zhang: Huazhong University of Science and Technology
Tongtong Zhang: The Third People’s Hospital of Chengdu
Wen Kong: Huazhong University of Science and Technology
Cai Chen: Huazhong University of Science and Technology
Shu Zhang: Huazhong University of Science and Technology
Qilin Yu: Huazhong University of Science and Technology
Xuemei Fan: the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province
Shiwei Liu: the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province
Yanjun Liu: The Third People’s Hospital of Chengdu
Cong-Yi Wang: the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs from young APCs effectively inhibit M1 macrophage polarization. Accordingly, targeted liposomes are designed to deliver miR-145-5p mimics to ATMs, which effectively prevent the obesity in middle-aged mice. Collectively, our findings highlight the role of APC-derived EVs in midlife obesity and propose miR-145-5pas a promising therapeutic target for clinical applications.

Date: 2025
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DOI: 10.1038/s41467-025-57444-y

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