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

Pancreatic beta-cells adapt to compensate for increased metabolic demand during obesity. Although the miRNA pathway has an essential role in beta-cell expansion, whether it is involved in adaptive proliferation is largely unknown. First, we report that EGR2 binding to the miR-455 promoter induced miR-455 upregulation in the pancreatic islets of obesity mouse models. Then, in vitro gain- or lossof-function studies showed that miR-455 overexpression facilitated beta-cell proliferation. Knockdown of miR-455 in ob/ob mice via pancreatic intraductal infusion prevented compensatory beta-cell expansion. Mechanistically, our results revealed that increased miR-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 of Cdknlb mRNA, reducing the CDKN1B expression level and finally promoting beta-cell proliferation. Taken together, our results show that the miR-4551 CPEB1/CDKN1B pathway contributes to adaptive proliferation of beta-cells to meet metabolic demand during obesity.