Proximate causes for diet-induced obesity in laboratory mice: a case study.

Abstract

Detailed protocols and recommendations for the assessment of energy balance have been provided to address the problems associated with different body mass and body composition as apparent for mouse models in obesity research. Here, we applied these guidelines to investigate energy balance in two inbred mouse strains with contrasting susceptibilities for diet-induced obesity (DIO). Mice of the AKR/J strain are highly susceptible, whereas the SWR/J mice are almost completely resistant. The proximate mechanisms responsible for this striking phenotypic difference are only partially understood. Body mass and body composition, metabolizable energy, energy expenditure (EE), body temperature and spontaneous physical activity behavior were first assessed in a cohort of male AKR/J (N=29) and SWR/J (N=30) mice fed on a low-fat control diet (CD) to identify metabolic adaptations determining resistance to DIO. Thereafter, the immediate metabolic responses to high-fat diet (HFD) feeding for 3 days were investigated. Groups of weight-matched AKR/J (N=8) and SWR/J (N=8) mice were selected from the initial cohort for this intervention. Strain differences in body mass, fat mass and lean mass were adjusted by body mass as this was the only covariate significantly correlated with metabolizable energy and EE. On the CD, EE and fat oxidation was higher in SWR/J than in AKR/J mice, whereas no difference was found for metabolizable energy. In response to HFD feeding, both strains increased metabolizable energy intake, but also increased EE, body temperature, and fat oxidation. The catabolic adaptations to HFD feeding opposed the development of positive energy balance. Increased EE was not due to increased spontaneous physical activity. A significant strain difference was found when balancing metabolizable energy and daily energy expenditure (DEE). The guidelines were applicable with some limitations related to the adjustment of differences in body composition. Metabolic phenotyping revealed that metabolizable energy, DEE and metabolic fuel selection all contribute to the development of DIO. Therefore, assessing both sides of the energy balance equation is essential to identify the proximate mechanisms.