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

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 (100 μg, 4 times in 2 weeks) in naïve mice or injected into hippocampus (5 μg, 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 naïve 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.