Obesity-Induced miR-455 Upregulation Promotes Adaptive Pancreatic β-Cell Proliferation Through the CPEB1/CDKN1B Pathway

Pancreatic β-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in β-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to themiR-455 promoter inducedmiR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or loss-of-function studies showed thatmiR-455 overexpression facilitated β-cell proliferation. Knockdown ofmiR-455 inob/ob mice via pancreatic intraductal infusion prevented compensatory β-cell expansion. Mechanistically, our results revealed that increasedmiR-455 expression inhibits the expression of its target cytoplasmic polyadenylation element binding protein 1 (CPEB1), an mRNA binding protein that plays an important role in regulating insulin resistance and cell proliferation. Decreased CPEB1 expression inhibits elongation of the poly(A) tail and the subsequent translation ofCdkn1b mRNA, reducing the CDKN1B expression level and finally promoting β-cell proliferation. Taken together, our results show that themiR-455/CPEB1/CDKN1B pathway contributes to adaptive proliferation of β-cells to meet metabolic demand during obesity.

Source: Diabetes - January 14, 2022 Category: Endocrinology Source Type: research