Lifelong Obesity in a Polygenic Mouse Model Prevents Age- and Diet-Induced Glucose Intolerance– Obesity Is No Road to Late-Onset Diabetes in Mice

Visceral obesity holds a central position in the concept of the metabolic syndrome characterized by glucose intolerance in humans. However, until now it is unclear if obesity by itself is responsible for the development of glucose intolerance.We have used a novel polygenic mouse model characterized by genetically fixed obesity (DU6) and addressed age- and high fat diet-dependent glucose tolerance.Phenotype selection over 146 generations increased body weight by about 2.7-fold in male 12-week DU6 mice (P<0.0001) if compared to unselected controls (Fzt:DU). Absolute epididymal fat mass was particularly responsive to weight selection and increased by more than 5-fold (P<0.0001) in male DU6 mice. At an age of 6 weeks DU6 mice consumed about twice as much food if compared to unselected controls (P<0.001). Absolute food consumption was higher at all time points measured in DU6 mice than in Fzt:DU mice. Between 6 and 12 weeks of age, absolute food intake was reduced by 15% in DU6 mice (P<0.001) but not in Fzt:DU mice. In both mouse lines feeding of the high fat diet elevated body mass if compared to the control diet (P