Obesity-induced upregulation of miR-483-5p impairs the function and identity of pancreatic ß-cells.
Diabetes Obes Metab
; 26(10): 4510-4521, 2024 Oct.
Article
em En
| MEDLINE
| ID: mdl-39072950
ABSTRACT
AIM:
To assess the expression and function of miR-483-5p in diabetic ß 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 ß cell-specific miR-483-5p downregulation were studied under metabolic stress (i.e. a high-fat diet) condition. Lineage tracing was used to determine ß-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 ß cells results in impaired insulin secretion and ß-cell identity. Cell lineage-specific analyses revealed that miR-483-5p overexpression deactivated ß-cell identity genes (insulin, Pdx1 and MafA) and derepressed ß-cell dedifferentiation (Ngn3) genes. miR-483-5p downregulation in ß 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 ß-cell maturation.CONCLUSIONS:
These findings indicate that the miR-483-5p-mediated reduction of mRNAs specifies ß-cell identity as a contributor to ß-cell dysfunction via the loss of cellular differentiation.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Regulação para Cima
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MicroRNAs
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Células Secretoras de Insulina
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Obesidade
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article