Dynamic Glucoregulation and Mammalian-Like Responses to Metabolic and Developmental Disruption in Zebrafish

Authors

Agata Jurczyk, University of Massachusetts Medical School
Nicole M. Roy, Sacred Heart UniversityFollow
Rabia Bajwa, University of Massachusetts Medical School
Philipp Gut, University of California - San Francisco
Kathryn Lipson, Western New England University
Chaoxing Yang, University of Massachusetts Medical School
Laurence Covassin, University of Massachusetts Medical School
Waldemar J. Racki, University of Massachusetts Medical School
Aldo A. Rossini, University of Massachusetts Medical School
Nancy Phillips, University of Massachusetts Medical School
Didier Y. R. Stainier, University of California - San Francisco
Dale L. Greiner, University of Massachusetts Medical School
Michael A. Brehm, University of Massachusetts Medical School
Rita Bortell, University of Massachusetts Medical School
Philip Diiorio, University of Massachusetts Medical School

Document Type

Peer-Reviewed Article

Publication Date

1-15-2011

Abstract

Zebrafish embryos are emerging as models of glucose metabolism. However, patterns of endogenous glucose levels, and the role of the islet in glucoregulation, are unknown. We measured absolute glucose levels in zebrafish and mouse embryos, and demonstrate similar, dynamic glucose fluctuations in both species. Further, we show that chemical and genetic perturbations elicit mammalian-like glycemic responses in zebrafish embryos. We show that glucose is undetectable in early zebrafish and mouse embryos, but increases in parallel with pancreatic islet formation in both species. In zebrafish, increasing glucose is associated with activation of gluconeogenic phosphoenolpyruvate carboxykinase1 (pck1) transcription. Non-hepatic Pck1 protein is expressed in mouse embryos. We show using RNA in situ hybridization, that zebrafish pck1 mRNA is similarly expressed in multiple cell types prior to hepatogenesis. Further, we demonstrate that the Pck1 inhibitor 3-mercaptopicolinic acid suppresses normal glucose accumulation in early zebrafish embryos. This shows that pre- and extra-hepatic pck1 is functional, and provides glucose locally to rapidly developing tissues. To determine if the primary islet is glucoregulatory in early fish embryos, we injected pdx1-specific morpholinos into transgenic embryos expressing GFP in beta cells. Most morphant islets were hypomorphic, not a genetic, but embryos still exhibited persistent hyperglycemia. We conclude from these data that the early zebrafish islet is functional, and regulates endogenous glucose. In summary, we identify mechanisms of glucoregulation in zebrafish embryos that are conserved with embryonic and adult mammals. These observations justify use of this model in mechanistic studies of human metabolic disease.

Comments

Published in final edited form in: Gen Comp Endocrinol. 2011 January 15; 170(2): 334–345. doi:10.1016/j.ygcen.2010.10.010.

Version posted is the NIH Public Access Author Manuscript.

DOI

10.1016/j.ygcen.2010.10.010

PubMed ID

20965191

Recommended Citation

Jurczyk, Agata et al. "Dynamic Glucoregulation and Mammalian-Like Responses to Metabolic and Developmental Disruption in Zebrafish." Gen Comp Endocrinol. 170.2 (2011): 334–345.