Circulating exosome-like vesicles of humans with nondiabetic obesity impaired isletβ-cell proliferation,which was associated with decreased Omentin-1 protein cargo

The regulation ofβ-cell mass in the status of nondiabetic obesity remains not well understood.We aimed to investigate the role of circulating exosome-like vesicles(ELVs)isolated from humans with simple obesity in the regulation of isletβ-cell mass.Between June 2017 and July 2019,81 subjects with simple obesity and 102 healthy volunteers with normal weight were recruited.ELVs were isolated by ultra-centrifugation.The proliferations ofβ-cells and islets were measured by 5-ethynl-2′-deoxyuridine(EdU).Protein components in ELVs were identified by Quantitative Proteomic Analysis and verified by Western blot and ELISA.The role of specific exosomal protein was analyzed by gain-of-function approach in ELVs released by 3T3-L1 preadipocytes.Circulating ELVs from subjects with simple obesity inhibitedβ-cell proliferation in vitro without affecting its apoptosis,secretion,and inflammation.The protein levels of Rictor and Omentin-1 were downregulated in circulating ELVs from subjects with simple obesity and associated with the obesity-linked pathologic conditions.The ELV-carried Omentin-1 and Omentin-1 protein per se were validated to increaseβ-cell proliferation and activate Akt signaling pathway.Moreover,Omentin-1 in ELVs was downregulated by insulin.The circulating ELVs may act as a negative regulator forβ-cell mass in nondiabetic obesity through inhibitingβ-cell proliferation.This effect was associated with downregulated Omentin-1 protein in ELVs.This newly identified ELV-carried protein could be a mediator linking insulin resistance to impairedβ-cell proliferation and a new potential target for increasingβ-cell mass in obesity and T2DM.