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
-
- Zebrafish/genetics
- Zebrafish/metabolism
- RNA, Messenger
- Animals
- Receptors, Glucagon*/genetics
- PubMed
- 36334626 Full text @ J. Biol. Chem.
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