Adipocyte-derived extracellular vesicles are key regulators of central leptin sensitivity and energy homeostasis

作者：Jin Wang, Xuhong Zhang, Ye Zhu, Haixiang Sun, Xuetao Chen, Zhicong Zhao, Nina Zhang, Chenyu Zhang, Liang Li, Yan Bi · 发表于：Cell Metabolism · 年份：2025 · DOI：10.1016/j.cmet.2025.10.005 · 被引用次数：17 · 研究领域：Extracellular vesicles in disease、Regulation of Appetite and Obesity、Adipokines, Inflammation, and Metabolic Diseases

The exact mechanisms underlying leptin resistance, the central mechanism of obesity, remain elusive. Herein, we demonstrate that adipocyte-derived extracellular vesicles (Ad-EVs) serve as key regulatory factors of hypothalamic circuits governing food intake and body weight by modulating leptin responsiveness. Specifically, we identified a subset of microRNA (miRNA) within Ad-EVs that exerts leptin-sensitizing effects by inhibiting negative feedback regulators of leptin receptor signaling. Loss of these leptin-sensitizing miRNAs in Ad-EVs contributes to leptin resistance and subsequent weight gain in obesity. Of note, we developed engineered EVs modified with specific Ad-EV membrane proteins for targeted delivery of leptin-sensitizing miRNAs to the central nervous system, which reversed central leptin resistance and induced significant weight loss in obese mice. These findings highlight the critical role of Ad-EVs in central leptin sensitivity regulation, offering new insights into the role of the adipose tissue-brain axis in maintaining energy balance and potential pharmacological targets for obesity treatment.