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

下调和上调 医学 功能(生物学) 身份(音乐) 肥胖 细胞生物学 内分泌学 生物化学 基因 生物 物理 声学
作者
Hongyu Yuan,Mei He,Qinnan Yang,Fandi Niu,Yuchen Zou,Haibo Liu,Yang� Yang,Aiming Liu,Xiaoai Chang,Fang Chen,Tijun Wu,Han Xiao,Yaqin Zhang
出处
期刊:Diabetes, Obesity and Metabolism [Wiley]
标识
DOI:10.1111/dom.15805
摘要

Abstract Aim To assess the expression and function of miR‐483‐5p in diabetic β cells. Methods The 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. Results miR‐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. Conclusions These 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.
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