Obesity is influenced by both genetics and diet and has wide ranging comorbidities, including anxiety and depressive disorders. In this study, outbred Heterogeneous Stock (HS) rats were fed high fat diet (HFD) or low fat diet (LFD) and tested for metabolic and behavioral outcomes. Male HS rats were fed 60% HFD or 10% LFD ad lib for 12-21 weeks. Rats were weighed weekly. We assessed multiple metabolic (glucose tolerance, fasting insulin, fat pad weights) and behavioral (elevated plus maze - EPM, open field test - OFT, splash test - SpT, and forced swim test - FST) measures. 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 coping response to stress and/or despair- and anxiety-like behaviors, including increased closed arm time and decreased open arm time in the EPM, increased movement and rest episodes and decreased rearing episodes in the OFT, increased SpT grooming time, and increased FST immobility. Positive correlations were found between FST immobility and visceral fat pad weights. We also found diet-dependent correlations between EPM, OFT and SpT measures. HFD negatively affected metabolic and behavioral health in HS rats. Changes in multiple coping/despair-and anxiety-like behaviors, independent of locomotion, indicate a role of HFD on behavioral health beyond just fat mass. This work establishes the HS rat as a model to study gene by diet interactions affecting obesity and behavioral health.

Obesity is a growing epidemic associated with a range of comorbidities, including depression and anxiety. Increasing evidence in humans suggests shared genetics underlying obesity and mental health, in addition to environmental factors, such as diet, playing a role in both. To better understand gene by diet interactions on adiposity and behavior, we propose the use of outbred heterogeneous stock (HS) rats. HS rats were created through random mating of 8 inbred strains and then maintained in a way that minimizes inbreeding. The resulting population allows for genetic fine‐mapping of complex traits, with each rat being genetically and phenotypically unique. The current study assesses how high fat diet (HFD) affects metabolic outcomes and emotional behavior in this model.In an initial study, we assessed the role of HFD or low fat diet (LFD) consumption on metabolic health and behavioral despair. After 8 weeks of HFD or LFD consumption, we administered an intraperitoneal glucose tolerance test. After 10 weeks, we administered the forced swim test (FST), a measure of behavioral despair. Animals were euthanized after 12 weeks of diet consumption and fat pads were weighed. We found that HFD increased body weight and visceral fat pad weight, reduced glucose tolerance, and increased fasting insulin compared to LFD. Although HFD had no effect on immobility in the FST, there was a significant positive correlation between fat pad weight and behavioral despair. To determine if this correlation was driven by emotional health or physical limitations, we ran a second study in which 64 HS rats were placed on a HFD or LFD and we then conducted behavioral testing for anxiety and despair after 8–12 weeks and again after 17–19 weeks of diet consumption. Tests for anxiety included elevated plus maze (EPM) and open field test (OFT). Tests for despair included splash test (ST) and forced swim test (FST). Visceral fat pads were collected after 21 weeks on diet. In this second study, we found that HFD significantly increased immobility in the FST and increased movement and rest time in the OFT. Both FST immobility and OFT hyperactivity correlated with visceral fat pad weight, but only in HFD animals, indicating an effect of diet beyond weight gain in this cohort. Interestingly, despite the significant effects of HFD on both metabolic and mental health, many HS rats fell within the normal range of adiposity and behavior, suggesting gene by diet interactions may be playing a role in this population.In summary, we have shown that HS rats are susceptible to negative metabolic and behavioral effects of HFD, but a sub‐set of HS rats are protected, indicating that the HS rat may be an ideal model to investigate gene by diet interactions on obesity and mental health.Support or Funding InformationCenter for Diabetes, Obesity and Metabolism Pilot Grant, Wake Forest University School of MedicineThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Obesity is a growing epidemic associated with a range of comorbidities, including anxiety and depression. Genetics and environmental factors such as diet contribute to both adiposity and anxiety/depression. Heterogeneous stock (HS) rats are an outbred colony and useful for genetic mapping of complex traits. We have previously shown that HS male rats exhibit worsened metabolic and behavioral health in response to high fat diet (HFD). This study aims to determine if females have similar response to diet and if response to diet interacts with genetic background. We measured multiple metabolic (body weight, fat pad weight, glucose tolerance, fasting glucose and insulin) and behavioral (elevated plus maze, open field test, and forced swim test) outcomes in a large cohort of male and female rats on either HFD or low fat diet (LFD). We estimated overall heritability as well as heritability of response to diet for each outcome. Both sexes showed worsened metabolic measures when fed HFD compared to LFD. In contrast, only males exhibited altered behavioral responses to HFD relative to LFD, with no effect in females. Most metabolic and behavioral measures showed overall heritability in both sexes. In contrast, although there was some evidence for gene by diet (GxD) interactions for behavioral measures in males, GxD interactions were generally not found for the metabolic measures. These data demonstrate an important role of diet, sex and genetics in metabolic and behavioral phenotypes in HS rats, with a potential role of gene by diet interactions for behavioral outcomes only in males.