High Fat Diet Negatively Impacts both Metabolic and Emotional Health in an Outbred Rat Model

Abstract

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.