Visceral adipocyte-derived extracellular vesicle miR-27a-5p elicits glucose intolerance by inhibiting pancreatic b-cell insulin secretion
Pancreatic ß-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic ß-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in ß-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic ß-cell dysfunction in obesity-associated type 2 diabetes mellitus. Overall design: Total RNA from islets of NCD and HFD mice was isolated using the RNeasy mini kit (Qiagen), following the protocol for total RNA isolation. RNA integrity and concentration were assessed using an RNA Nano 6000 Assay Kit for the Bioanalyzer 2100 system (Agilent Technologies, Santa Clara, CA), according to the manufacturer's instructions.