1. Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.
- Author
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Zhang Y, Qian B, Yang Y, Niu F, Lin C, Yuan H, Wang J, Wu T, Shao Y, Shao S, Liu A, Wu J, Sun P, Chang X, Bi Y, Tang W, Zhu Y, Chen F, Su D, and Han X
- Subjects
- Animals, Mice, Insulin metabolism, Male, Obesity metabolism, Obesity genetics, Mice, Inbred C57BL, Mice, Obese, MicroRNAs metabolism, MicroRNAs genetics, Insulin-Secreting Cells metabolism, Glucose Intolerance metabolism, Glucose Intolerance genetics, Extracellular Vesicles metabolism, Insulin Secretion physiology, Intra-Abdominal Fat metabolism
- Abstract
Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of 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 improved insulin secretion and glucose intolerance in db/db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus., (© 2024 by the American Diabetes Association.)
- Published
- 2024
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