Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse

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.

Fig 1. The effects of initial weight and diet on body weight, glucose and insulin levels.

The top figures illustrate Body weight gains of animals on the Chow diet (A) and HFD (B). The middle panels (C, D) demonstrate the effects of the two diets on glucose levels. Insulin levels in Chow (E) and HFD (F) groups are illustrated in bottom panels. The * (A, B) indicates that all weight groups are statistically different from each other at all of the time-points with each diet. Statistical differences from the other groups (C-F) are identified by * while the ⁺ sign identifies differences between the highest and lowest values (two-way ANOVA followed by Sidak’s multiple comparison test, * or ⁺ p < .05). Additional differences between diets in each weight category are summarized in the text.

Fig 2. The effects of initial weight and diet on fasting glucose and glucose disposal in an OGTT.

The top figures show glucose responses in the OGTT for mice fed the Chow diet (A) and the HFD. Baseline glucose levels, after a 17 hour fast in the Low, Mid and High BW groups of mice fed the Chow diet (C) while glucose levels are significantly higher in the Mid BW and High BW animals on the HFD (D). The figures in the two lower panels illustrate the glucose AUC from the OGTT for animals in each of the body weight groups when fed Chow diet (E) and HFD (F). (one-way ANOVA followed by Sidak’s multiple comparison tests. ⁺ denotes a statistical difference compared to the Low BW and * denotes statistical from all other group, p < .05).

Fig 3. The effects of initial weight and diet on insulin levels during the OGTT.

This graph illustrates the insulin response to a glucose load at 18 weeks in the Low BW, Mid BW and High BW groups when fed the Chow diet (A) or the HFD (B). The * (A, B) indicates significant increases from baseline for that group (two-way ANOVA followed by Sidak’s multiple comparison tests). The insulin AUCs (C, D) for the above OGTTs (A, B) are also illustrated; the ** indicates a significant difference between the Low BW group and the other two groups (one-way ANOVA followed by Sidak’s multiple comparison tests). The lowest panel (E) illustrates the insulin content of the pancreas from the different weight groups on the two diets at 21 weeks. The effect of diets was tested in respective weight pairs (High BW, Mid BW and High BW); † denotes there was a statistically significance difference between the two diets in the High BW groups (one-way ANOVA followed by Sidak’s multiple comparison tests). *, **, † denotes statistical significance at the level p < .05).

Fig 4. Weight correlated with glucose and insulin.

Glucose (A) and insulin (B) levels at 14 weeks were plotted and analyzed according to the animal weights at 6 weeks of age (weight vs glucose, r = 0.7033, p < .0001; weight vs insulin, r = 0.5317, p < .0001).

Fig 5. Leptin levels and the effect of leptin on food intake.

Leptin levels (A) and the effect of leptin on food intake (B) at two ages are illustrated in this figure (one-way ANOVA followed by Sidak’s multiple comparison tests). Statistical differences from the other groups are denoted at p < .001(**) and p < .0001(***).