Glucose Dysregulation and Response to Common Anti-Diabetic Agents in the FATZO/Pco Mouse

PLoS One. 2017 Jun 22;12(6):e0179856. doi: 10.1371/journal.pone.0179856. eCollection 2017.

Abstract

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide.

Conclusion: Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.

MeSH terms

  • Adipose Tissue / drug effects
  • Animals
  • Body Weight / drug effects
  • Disease Models, Animal
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucose / metabolism*
  • Homeostasis / drug effects
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice
  • Triglycerides / blood

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Triglycerides
  • Glucose

Grant support

This project was partially funded by an SBIR grant from NIH (2R44DK082065) to PreClinOmics. Additional funding was supplied by Eli Lilly and Company in the form of salaries for authors MDM, PJE, JAF and TC but it did not have any additional role in the study design, data collection and analysis. There was also a contract from Eli Lilly and Company to do the semaglutide experiment. Funding was also supplied by PreClinOmics (now Crown Bioscience – Indiana) for authors CVJ, KMZ, and RGP in the form of salaries and other compensation. RGP was one of the owners and CSO for PreClinOmics and was the principal investigator on the SBIR grants and as such was responsible for the animal model development before, during and after the tenure of the SBIR funding and as such, was involved in study design, data collection, data analysis and manuscript production. CVJ is the general manager and CSO of Crown Bioscience – Indiana and as such, since March 2016, was partially responsible for the continued support of the project in the form of material, salaries study design, data collection, data analysis and manuscript production. The other specific roles of these authors are articulated in the “author contributions” section.