High-fat diet negatively impacts both metabolic and behavioral health in outbred heterogeneous stock rats.

Obesity is influenced by genetics and diet and has wide ranging comorbidities, including anxiety and depressive disorders. Outbred heterogeneous stock (HS) rats are used for fine-genetic mapping of complex traits and may be useful for understanding gene by diet interactions. In this study, HS rats were fed diets containing 60% kcal from fat (high-fat diet, HFD) or 10% kcal from fat (low-fat diet, LFD) and tested for metabolic (study 1) and behavioral (study 2) outcomes. In study 1, we measured glucose tolerance, fasting glucose and insulin, fat pad weights and despair-like behavior in the forced swim test (FST). In study 2, we assessed anxiety-like (elevated plus maze, EPM; open field test, OFT) and despair-like/coping (splash test, SpT; and FST) behaviors. Body weight and food intake were measured weekly in both studies. We found negative effects of HFD on metabolic outcomes, including increased body weight and fat pad weights, decreased glucose tolerance, and increased fasting insulin. We also found negative effects of HFD on despair-like/coping and anxiety-like behaviors. These include increased immobility in the FST, decreased open arm time in the EPM, and increased movement and rest episodes and decreased rearing in the OFT. The diet-induced changes in EPM and OFT were independent of overall locomotion. Additionally, diet-induced changes in OFT behaviors were independent of adiposity, while adiposity was a confounding factor for EPM and FST behavior. This work establishes the HS as a model to study gene by diet interactions affecting metabolic and behavioral health.