Grupo Obesidómica, Área de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.
Unidad de Proteómica, Instituto de Investigación Sanitaria de Santiago (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain.
Transl Res. 2022 Jan;239:85-102. doi: 10.1016/j.trsl.2021.01.006. Epub 2021 Jan 17.
Extracellular vesicles (EVs) have been recently postulated as key players in metabolic disorders emerging as an alternative way of paracrine/endocrine communication. However, the nature of EVs shed by adipose tissue (AT) and their role in obesity is still very limited. Here, we isolated human morbid obese visceral (VAT) and subcutaneous (SAT) whole AT shed EVs from donors submitted to bariatric surgery to characterize their protein cargo by qualitative and quantitative/SWATH mass spectrometry analysis. We identified 574 different proteins shed by morbid obese VAT and 401 proteins in those from SAT, establishing the first obese AT EV proteome reference map. Only 50% of identified proteins in VAT vesicles were common to those in SAT; additionally, EVs shed by obese VAT showed more AT and obesity-related adipokines than SAT. Functional classification shows that obese VAT vesicles exhibit an enrichment of proteins implicated in AT inflammation and insulin resistance such as TGFBI, CAVN1, CD14, mimecan, thrombospondin-1, FABP-4 or AHNAK. Selected candidate biomarkers from the quantitative-SWATH analysis were validated in EVs from independent morbid obese and from moderate obese to lean individuals showing that morbid obese VAT vesicles are characterized by a diminution of syntenin 1 and the elevation of TGFBI and mimecan. Interestingly, TGFBI and mimecan containing vesicles could be detected and quantified at circulating level in plasma. Thus, a significant elevation of -TGFBI-EVs was detected on those obese patients with a history of T2D compared to nondiabetic, and an augmentation of mimecan-EVs in obese plasma compared to those in healthy lean individuals. Thus, we conclude that obese AT release functional EVs carrying AT and obesity candidate biomarkers which vary regarding the AT of origin. Our findings suggest that circulating EV-TGFBI may facilitate monitoring T2D status in obese patients, and EV-mimecan may be useful to track adiposity, and more precisely, visceral obesity.
细胞外囊泡 (EVs) 最近被认为是代谢紊乱的关键参与者，是旁分泌/内分泌通讯的另一种方式。然而，脂肪组织 (AT) 释放的 EV 的性质及其在肥胖中的作用仍然非常有限。在这里，我们从接受减肥手术的供体中分离出人病态肥胖内脏 (VAT) 和皮下 (SAT) 全 AT 释放的 EV，通过定性和定量/SWATH 质谱分析来表征其蛋白质货物。我们鉴定了肥胖 VAT 释放的 574 种不同蛋白质和 SAT 中的 401 种蛋白质，建立了肥胖 AT EV 蛋白质组参考图谱。在 VAT 囊泡中鉴定出的 50%的蛋白质与 SAT 中的蛋白质相同；此外，肥胖 VAT 释放的 EV 比 SAT 释放的 EV 具有更多的与肥胖相关的脂肪因子。功能分类表明，肥胖 VAT 囊泡表现出与 AT 炎症和胰岛素抵抗相关的蛋白质的富集，如 TGFBI、CAVN1、CD14、mimecan、血小板反应蛋白-1、FABP-4 或 AHNAK。从定量 SWATH 分析中选择的候选生物标志物在来自独立病态肥胖和从中度肥胖到瘦个体的 EV 中进行验证，表明病态肥胖 VAT 囊泡的特征是 syntenin 1 的减少和 TGFBI 和 mimecan 的升高。有趣的是，TGFBI 和 mimecan 包含的囊泡可以在血浆中检测到并定量。因此，与非糖尿病患者相比，在有 T2D 病史的肥胖患者中检测到 -TGFBI-EVs 的显著升高，并且与健康瘦个体相比，肥胖患者血浆中的 mimecan-EVs 增加。因此，我们得出结论，肥胖 AT 释放具有 AT 和肥胖候选生物标志物的功能性 EV，这些标志物因起源的 AT 而异。我们的研究结果表明，循环 EV-TGFBI 可能有助于监测肥胖患者的 T2D 状态，而 EV-mimecan 可能有助于跟踪肥胖症，更准确地说是内脏肥胖症。
