南京中医药大学胡刚课题组近日取得一项新成果。经过不懈努力，他们的研究显示，内脏脂肪组织来源的细胞外囊泡通过miR-140-5p促进肥胖小鼠的应激易感性。相关论文发表在2025年2月10日出版的《中国药理学报》杂志上。

在这项研究中，研究小组研究了内脏脂肪组织（VAT）对肥胖小鼠应激敏感性的影响，VAT是肥胖的一个重要特征。年龄匹配的小鼠分别饲喂鼠粮（CD）和高脂饲料（HFD） 12周。剥夺CD小鼠的VAT，移植HFD小鼠（TransHFD）或CD小鼠（TransCD）的VAT。从CD或HFD小鼠的VAT中制备细胞外囊泡（EVs），并静脉注射(100μg， 2周4次)小鼠或注射到海马(5μg， 2周内4次)。移植后14天评估抑郁样行为。

课题组研究人员发现，HFD小鼠表现出明显更高的体重增加，胰岛素和葡萄糖耐量受损，并伴有应激敏感性增加。移植来自HFD小鼠的VAT或VAT衍生的EVs可引起突触损伤并促进受体小鼠的应激敏感性。通过抑制VAT中miRNA的生物发生和miRNA测序分析，研究组发现miR-140-5p在HFD小鼠VAT- EVs和海马区均显著上调。海马miR-140-5p在nave小鼠不仅促进了急性应激性抑郁样行为，而且降低了海马CREB-BDNF信号级联和突触可塑性。相反，HFD小鼠的VAT、VAT- EVs或海马组织中miR-140-5p的敲低可以防止急性应激，降低通过CREB-BDNF途径介导的应激敏感性。

综上所述，肥胖小鼠的VAT- EVs或运输的miRNAs促进突触损伤和应激易感性，为代谢相关情感障碍提供了潜在的治疗靶点。

据了解，肥胖会增加患抑郁症的风险。有证据表明，外周炎症、血糖失调和下丘脑-垂体-肾上腺轴的过度活跃与肥胖和抑郁都有关系。

附：英文原文

Title: Visceral adipose tissue-derived extracellular vesicles promote stress susceptibility in obese mice via miR-140-5p

Author: Wang, Hao, Zhang, Li, Yang, Wan-yue, Ji, Xiao-yi, Gao, An-qi, Wei, Yi-hong, Ding, Xin, Kang, Yue, Ding, Jian-hua, Fan, Yi, Lu, Ming, Hu, Gang

Issue&Volume: 2025-02-10

Abstract: Obesity increases the risk of depression. Evidence shows that peripheral inflammation, glycemic dysregulation, and hyperactivity within the hypothalamic-pituitary-adrenal axis are implicated in both obesity and depression. In this study we investigated the impact of visceral adipose tissue (VAT), a crucial characteristic of obesity, on stress susceptibility in obese mice. Age-matched mice were fed with chow diet (CD) or high-fat diet (HFD), respectively, for 12 weeks. CD mice were deprived of VAT and received transplantation of VAT from HFD mice (TransHFD) or CD mice (TransCD). Extracellular vesicles (EVs) were prepared from VAT of CD or HFD mice, and intravenously injected (100μg, 4 times in 2 weeks) in nave mice or injected into hippocampus (5μg, 4 times in 2 weeks) through implanted bilateral cannula. Depression-like behaviors were assessed 14 days after transplantation. We showed that HFD mice exhibited significantly higher body weight gain and impaired insulin and glucose tolerance, accompanied by increased stress susceptibility. Transplantation of VAT or VAT-derived EVs from HFD mice caused synaptic damage and promoted stress susceptibility in recipient mice. Through inhibiting miRNA biogenesis in the VAT and miRNA sequencing analysis, we demonstrated that miR-140-5p was significantly upregulated in both VAT-EVs and hippocampus of HFD mice. Overexpression of hippocampal miR-140-5p in nave mice not only facilitated acute stress-induced depression-like behaviors, but also decreased hippocampal CREB-BDNF signaling cascade and synaptic plasticity. Conversely, knockdown of miR-140-5p in the VAT, VAT-EVs or hippocampus of HFD mice protected against acute stress, reducing stress susceptibility that were mediated via CREB-BDNF pathway. In summary, VAT-EVs or the cargo miRNAs in obese mice promote synaptic damage and stress susceptibility, providing potential therapeutic targets for metabolism-related affective disorders.

DOI: 10.1038/s41401-025-01484-z

Source: https://www.nature.com/articles/s41401-025-01484-z