Visceral adipocyte-derived extracellular vesicle miR-27a-5p elicits glucose intolerance by inhibiting pancreatic b-cell insulin secretion

ABSTRACT Pancreatic b-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 b-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca²⁺ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in b-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 b-cell dysfunction in obesity-associated type 2 diabetes mellitus. KEYWORDS: visceral adipocyte, β-cell, EVs, miR-27a-5p, insulin secretion Word count: 6176 Article Highlights l miR-27a-5p expression in the islets is increased in obese-associated diabetes mouse models. l miR-27a-5p overexpression in β-cells impairs β-cell function in vitro and in vivo. l Visceral adipocyte-derived extracellular vesicles (EVs) and their cargo miR-27a-5p lead to b-cell insulin secretion injury and glucose intolerance by targeting Cacna1c. l Blockage of visceral adipocyte EVs’ miR-27a-5p expression improves β-cell insulin secretion and glucose tolerance in db/db mice.