Abstract
Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes.
MeSH terms
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Animals
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Blood Glucose / metabolism
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Body Weight*
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Diabetes Mellitus, Type 2 / etiology*
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / physiopathology
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Diet, High-Fat / adverse effects*
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Eating
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Insulin / metabolism
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Leptin / metabolism
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Male
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Mice
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Obesity / etiology*
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Obesity / metabolism
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Obesity / physiopathology
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Pancreas / metabolism
Substances
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Blood Glucose
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Insulin
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Leptin
Grants and funding
This project was partially funded by an SBIR grant from NIH (2R44DK082065) to PreClinOmics. The remainder of the funding was supplied by Eli Lilly and Company in the form of salaries for authors BAD, BLS, MDM, PJE, and TC but it did not have any additional role in the study design, data collection and analysis. 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.