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

Autor: Yuan H; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., He M; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Yang Q; The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Niu F; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Zou Y; The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Liu C; The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Yang Yang; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Liu A; The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, China., Chang X; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Chen F; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Wu T; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Han X; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China., Zhang Y; Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2024 Oct; Vol. 26 (10), pp. 4510-4521. Date of Electronic Publication: 2024 Jul 29.
DOI: 10.1111/dom.15805
Abstrakt: 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.
(© 2024 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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