Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation
Abstract Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the lack of therapeutics effectively targeting beta cell proliferation, other targetable pathwa...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-04-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202013524 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849331923794526208 |
|---|---|
| author | Jian Ma Bowen Xing Yan Cao Xin He Kate E Bennett Chao Tong Chiying An Taylor Hojnacki Zijie Feng Sunbin Deng Sunbin Ling Gengchen Xie Yuan Wu Yue Ren Ming Yu Bryson W Katona Hongzhe Li Ali Naji Xianxin Hua |
| author_facet | Jian Ma Bowen Xing Yan Cao Xin He Kate E Bennett Chao Tong Chiying An Taylor Hojnacki Zijie Feng Sunbin Deng Sunbin Ling Gengchen Xie Yuan Wu Yue Ren Ming Yu Bryson W Katona Hongzhe Li Ali Naji Xianxin Hua |
| author_sort | Jian Ma |
| collection | DOAJ |
| description | Abstract Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the lack of therapeutics effectively targeting beta cell proliferation, other targetable pathways need to be identified. Herein, we show that Pbk, a serine/threonine protein kinase, is essential for high fat diet (HFD)‐induced beta cell proliferation in vivo using a Pbk kinase deficiency knock‐in mouse model. Mechanistically, JunD recruits menin and HDAC3 complex to the Pbk promoter to reduce histone H3 acetylation, leading to epigenetic repression of Pbk expression. Moreover, menin inhibitor (MI) disrupts the menin–JunD interaction and augments Pbk transcription. Importantly, MI administration increases beta cell proliferation, ameliorating hyperglycemia, and impaired glucose tolerance (IGT) in HFD‐induced diabetic mice. Notably, Pbk is required for the MI‐induced beta cell proliferation and improvement of IGT. Together, these results demonstrate the repressive role of the menin/JunD/Pbk axis in regulating HFD‐induced compensatory beta cell proliferation and pharmacologically regulating this axis may serve as a novel strategy for type 2 diabetes therapy. |
| format | Article |
| id | doaj-art-d764a053a59a49c5a1e44e7b4becb24f |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-d764a053a59a49c5a1e44e7b4becb24f2025-08-20T03:46:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-04-0113512210.15252/emmm.202013524Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferationJian Ma0Bowen Xing1Yan Cao2Xin He3Kate E Bennett4Chao Tong5Chiying An6Taylor Hojnacki7Zijie Feng8Sunbin Deng9Sunbin Ling10Gengchen Xie11Yuan Wu12Yue Ren13Ming Yu14Bryson W Katona15Hongzhe Li16Ali Naji17Xianxin Hua18Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDivision of Gastroenterology, University of Pennsylvania Perelman School of MedicineDepartment of Biology, University of PennsylvaniaDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Chemistry, University of PennsylvaniaDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Biochemistry and Biophysics, University of Pennsylvania Perelman School of MedicineInstitute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineDepartment of Biochemistry and Biophysics, University of Pennsylvania Perelman School of MedicineInstitute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of MedicineDepartment of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of MedicineAbstract Pancreatic beta cells undergo compensatory proliferation in the early phase of type 2 diabetes. While pathways such as FoxM1 are involved in regulating compensatory beta cell proliferation, given the lack of therapeutics effectively targeting beta cell proliferation, other targetable pathways need to be identified. Herein, we show that Pbk, a serine/threonine protein kinase, is essential for high fat diet (HFD)‐induced beta cell proliferation in vivo using a Pbk kinase deficiency knock‐in mouse model. Mechanistically, JunD recruits menin and HDAC3 complex to the Pbk promoter to reduce histone H3 acetylation, leading to epigenetic repression of Pbk expression. Moreover, menin inhibitor (MI) disrupts the menin–JunD interaction and augments Pbk transcription. Importantly, MI administration increases beta cell proliferation, ameliorating hyperglycemia, and impaired glucose tolerance (IGT) in HFD‐induced diabetic mice. Notably, Pbk is required for the MI‐induced beta cell proliferation and improvement of IGT. Together, these results demonstrate the repressive role of the menin/JunD/Pbk axis in regulating HFD‐induced compensatory beta cell proliferation and pharmacologically regulating this axis may serve as a novel strategy for type 2 diabetes therapy.https://doi.org/10.15252/emmm.202013524beta cellcompensatory proliferationdiabetesmeninPbk |
| spellingShingle | Jian Ma Bowen Xing Yan Cao Xin He Kate E Bennett Chao Tong Chiying An Taylor Hojnacki Zijie Feng Sunbin Deng Sunbin Ling Gengchen Xie Yuan Wu Yue Ren Ming Yu Bryson W Katona Hongzhe Li Ali Naji Xianxin Hua Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation EMBO Molecular Medicine beta cell compensatory proliferation diabetes menin Pbk |
| title | Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation |
| title_full | Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation |
| title_fullStr | Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation |
| title_full_unstemmed | Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation |
| title_short | Menin‐regulated Pbk controls high fat diet‐induced compensatory beta cell proliferation |
| title_sort | menin regulated pbk controls high fat diet induced compensatory beta cell proliferation |
| topic | beta cell compensatory proliferation diabetes menin Pbk |
| url | https://doi.org/10.15252/emmm.202013524 |
| work_keys_str_mv | AT jianma meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT bowenxing meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT yancao meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT xinhe meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT kateebennett meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT chaotong meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT chiyingan meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT taylorhojnacki meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT zijiefeng meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT sunbindeng meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT sunbinling meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT gengchenxie meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT yuanwu meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT yueren meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT mingyu meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT brysonwkatona meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT hongzheli meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT alinaji meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation AT xianxinhua meninregulatedpbkcontrolshighfatdietinducedcompensatorybetacellproliferation |