Obesity‐induced upregulation of miR‐483‐5p impairs the function and identity of pancreatic β‐cells

Abstract

AbstractAimTo assess the expression and function of miR‐483‐5p in diabetic β cells.MethodsThe expression of miR‐483‐5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual‐luciferase activity, and western blotting assays, were utilized for miR‐483‐5p target gene verification. Mice with β cell‐specific miR‐483‐5p downregulation were studied under metabolic stress (i.e. a high‐fat diet) condition. Lineage tracing was used to determine β‐cell fate.ResultsmiR‐483‐5p increased in the islets of obese mouse models. Expression levels of miR‐483‐5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR‐483‐5p in β cells results in impaired insulin secretion and β‐cell identity. Cell lineage‐specific analyses revealed that miR‐483‐5p overexpression deactivated β‐cell identity genes (insulin, Pdx1 and MafA) and derepressed β‐cell dedifferentiation (Ngn3) genes. miR‐483‐5p downregulation in β cells of high‐fat diet‐fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR‐483‐5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β‐cell maturation.ConclusionsThese findings indicate that the miR‐483‐5p–mediated reduction of mRNAs specifies β‐cell identity as a contributor to β‐cell dysfunction via the loss of cellular differentiation.