ATF4 is the main transcriptional regulator of the Unfolded Protein Response (UPR) that promote restoration of normal ER function, although the contribution of ATF4 on β-cells remains poorly understood. Therefore, we developed mature β-cell specific ATF4 knockout mice (βATF4KO), were crossed with mice expressing Cre recombinase under the control of insulin promoter. ATF4-deleted β-cells were comparable to WT under normal condition but were susceptible to ER stress. To examine the role of ATF4 in vivo, we bred the Akita insulin folding mutation onto βATF4KO background. Akita/βATF4KO were dramatically compromised as shown by overt hyperglycemia in their early age and remarkable short life span due to ketoacidosis. Interestingly, we found that increased number of cells staining for glucagon, somatostatin or pancreatic polypeptide in the islets of Akita/βATF4KO, suggesting the increased β-cell dedifferentiation. We further employed the gain-of-function study using β-cell specific transgenic mice expressing Fv2E-PERK, which can activate PERK/ATF4 signaling upon addition of the artificial ligand. The induced activation of PERK/ATF4 signaling resulted in reduced insulin secretion without any sign of β-cell apoptosis. Microarray analysis revealed that several key β-cell specific transcription genes such as Pdx1 and MafA were inhibited by the activation of PERK/ATF4 signaling. We demonstrated that ATF4-deleted β-cells are more vulnerable to dedifferentiation during ER stress and excess ATF4 has inhibitory effect in β-cell function. Overall, our study has uncovered that the importance of ATF4 in governing β-cell adaptation and resilience during ER stress.


K. Kitakaze: None. K. Kurahashi: None. M. Miyake: None. Y. Hamada: None. M. Oyadomari: None. S. Oyadomari: None.

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