Wang Jin, Zhang Xuhong, Zhu Ye, Sun Haixiang, Chen Xuetao, Zhao Zhicong, Zhang Nina, Zhang Chenyu, Li Liang, Bi Yan
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
Cell Metab. 2026 Jan 6;38(1):82-99.e8. doi: 10.1016/j.cmet.2025.10.005. Epub 2025 Nov 11.
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.
瘦素抵抗作为肥胖的核心机制，其确切机制仍不清楚。在此，我们证明脂肪细胞衍生的细胞外囊泡（Ad-EVs）通过调节瘦素反应性，作为控制食物摄入和体重的下丘脑回路的关键调节因子。具体而言，我们在Ad-EVs中鉴定出一组微小RNA（miRNA），它们通过抑制瘦素受体信号的负反馈调节因子发挥瘦素增敏作用。Ad-EVs中这些瘦素增敏miRNA的缺失导致瘦素抵抗以及肥胖症患者随后的体重增加。值得注意的是，我们开发了用特定Ad-EV膜蛋白修饰的工程化囊泡，用于将瘦素增敏miRNA靶向递送至中枢神经系统，这逆转了中枢瘦素抵抗并导致肥胖小鼠显著体重减轻。这些发现突出了Ad-EVs在中枢瘦素敏感性调节中的关键作用，为脂肪组织-脑轴在维持能量平衡中的作用提供了新见解，并为肥胖症治疗提供了潜在的药理学靶点。
