Adipocyte-derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus
Adipocyte-derived extracellular vesicles modulate appetite and weight through mTOR signalling in the hypothalamus
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DOI：
10.1111/apha.13339
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发表时间：
2019-07-27
影响因子：
6.3
通讯作者：
Zhan, Xiaorong
中科院分区：
文献类型：
--
作者：
Gao, Jie;Li, Xinyu;Zhan, Xiaorong
目的2型糖尿病和肥胖症是与体内能量过剩有关的疾病。下丘脑和脂肪组织之间的异常相互作用是能量代谢障碍的关键触发因素。细胞外小泡(EVS)通过运输细胞内的货物到受体细胞来调节细胞间的通讯，从而改变受体细胞的功能。本研究旨在评估脂肪细胞来源的EV是否能作用于下丘脑神经元来调节能量摄入，并识别EV相关的非编码RNA。方法应用共聚焦成像技术追踪下丘脑POMC神经元摄取标记脂肪细胞来源的外切体的情况。应用实时定量聚合酶链式反应和免疫印迹技术检测脂肪细胞来源的EV对体外培养的POMC神经元mTOR信号转导通路的影响。此外，将脂肪细胞衍生的EV注射到受体小鼠中，并监测小鼠体重和每日摄食量的变化。探讨EV相关的MALAT1对POMC神经元的生物学作用。结果脂肪细胞来源的EV在体外成功地转移到POMC神经元。结果表明，肥胖小鼠的脂肪细胞分泌含有MALAT1的EVS，当给瘦小鼠服用时，这会增加食欲和体重。相反，来自瘦小鼠的脂肪细胞衍生的EV在给肥胖小鼠使用时减少了食物的摄入量和体重。结论脂肪细胞来源的EVS在介导脂肪细胞与下丘脑神经元之间的相互作用中起重要作用。脂肪细胞来源的EVS可以通过体内和体外的下丘脑mTOR信号调节POMC的表达，从而影响机体的能量摄入。
Aim Type 2 diabetes and obesity are diseases related to surplus energy in the body. Abnormal interaction between the hypothalamus and adipose tissues is a key trigger of energy metabolism dysfunction. Extracellular vesicles (EVs) regulate intercellular communication by transporting intracellular cargo to recipient cells thereby altering the function of recipient cells. This study aimed to evaluate whether adipocyte-derived EVs can act on hypothalamic neurons to modulate energy intake and to identify the EV-associated non-coding RNAs. Methods Confocal imaging was used to trace the uptake of labelled adipocyte-derived exosomes by hypothalamic anorexigenic POMC neurons. The effects of adipocyte-derived EVs on the mammalian target of rapamycin (mTOR) signalling pathway in POMC neurons were evaluated based on mRNA and protein expression in vitro using quantitative real-time PCR and western blotting. In addition, adipocyte-derived EVs were injected into recipient mice, and changes in mice body weight and daily food intake were monitored. The biological effects of the EV-associated MALAT1 on POMC neurons were explored. Results Adipocyte-derived EVs were successfully transferred into POMC neurons in vitro. Results showed that adipocytes of obese mice secreted MALAT1-containing EVs, which increased appetite and weight when administered to lean mice. Conversely, adipocyte-derived EVs from lean mice decreased food intake and weight when administered to obese mice. Conclusion Adipocyte-derived EVs play important roles in mediating the interaction between adipocytes and hypothalamic neurons. Adipocyte-derived EVs can regulate POMC expression through the hypothalamic mTOR signalling in vivo and in vitro, thereby affecting body energy intake.