PUBLICATION
Disruption of the glucagon receptor increases glucagon expression beyond α-cell hyperplasia in zebrafish
- Authors
- Kang, Q., Zheng, J., Jia, J., Xu, Y., Bai, X., Chen, X., Zhang, X.K., Wong, F.S., Zhang, C., Li, M.
- ID
- ZDB-PUB-221106-5
- Date
- 2022
- Source
- The Journal of biological chemistry 298(12): 102665 (Journal)
- Registered Authors
- Li, Mingyu
- Keywords
- Glucagon, Glucagon Receptor, Pancreatic α cells, Single-cell sequencing, Zebrafish
- Datasets
- GEO:GSE179894
- MeSH Terms
-
- Animals
- Glucagon*
- Hyperplasia
- RNA, Messenger
- Receptors, Glucagon*/genetics
- Receptors, Glucagon*/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 36334626 Full text @ J. Biol. Chem.
Citation
Kang, Q., Zheng, J., Jia, J., Xu, Y., Bai, X., Chen, X., Zhang, X.K., Wong, F.S., Zhang, C., Li, M. (2022) Disruption of the glucagon receptor increases glucagon expression beyond α-cell hyperplasia in zebrafish. The Journal of biological chemistry. 298(12):102665.
Abstract
The glucagon receptor (GCGR) is a potential target for diabetes therapy. Several emerging GCGR antagonism-based therapies are under pre-clinical and clinical development. However, GCGR antagonism, as well as genetically-engineered GCGR deficiency in animal models is accompanied by α-cell hyperplasia and hyperglucagonemia, which may limit the application of GCGR antagonism. To better understand the physiological changes in α cells following GCGR disruption, we performed single cell sequencing of α cells isolated from control and gcgr-/- (glucagon receptor deficient) zebrafish. Interestingly, beyond the α-cell hyperplasia, we also found that the expression of gcga, gcgb, pnoca and several glucagon-regulatory transcription factors were dramatically increased in one cluster of gcgr-/- α cells. We further confirmed that glucagon mRNA was upregulated in gcgr-/- animals by in situ hybridization, and that glucagon promoter activity was increased in gcgr-/-;Tg(gcga:GFP) reporter zebrafish. We also demonstrated that gcgr-/- α cells had increased glucagon protein levels, and increased granules after GCGR disruption. Intriguingly, the increased mRNA and protein levels could be suppressed by treatment with high-level glucose or knockdown of the pnoca gene. In conclusion, these data demonstrated that GCGR-deficiency not only induced α-cell hyperplasia but also increased glucagon expression in α cells, findings which provide more information about physiological changes in α-cells when the GCGR is disrupted.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping