SUN-093 Early Life Exposure to High Fat Diet Induces Extensive Changes in the Adult Brain

Abstract

Maternal environmental exposures, like high fat diets, diabetes and obesity, can induce long term programming in offspring, including metabolic abnormalities but also phenotypes associated with neurodevelopmental disorders (NDDs), such as autism spectrum disorder, anxiety and depression. However, previous studies have not fully assessed the mechanism(s) underlying these later life neurologic effects. We hypothesized that as part of the mechanism, maternal in utero and perinatal exposure to high fat diet would induce alterations in the structure of the adult brain. To test this hypothesis, we acclimated C57BL/6 mice for 6 weeks prior to breeding, with diets differing in fat percentage: control diet, with 10% of kcal from fat (CD); high fat diet, with 45 % of kcal from fat (HF45); and even higher fat diet, with 60% of kcal from fat (HF60). Mothers were maintained on their respective diets throughout gestation and lactation. At weaning, day (D) 21, all pups were switched to the CD until whole brain magnetic resonance imaging (MRI) was performed in adulthood, D65. MRI was also performed on mothers after weaning. Metabolic effects of the different diets on mothers and offspring were assessed throughout the study. We found that mothers fed HF60 but not HF45 gained weight compared to those fed CD during the initial acclimation. HF60 mothers also displayed glucose intolerance throughout the study period from acclimation through lactation. Among the offspring, male and female pups born from HF45 and HF60 diet weighed more at weaning than CD pups. Body weights converged among the male offspring by D35, while they continued to be higher in female offspring at D65. By the time of MRI, there were no differences in percentage body fat among all diets in both males and females. Having documented expected metabolic effects, we next analyzed the MRI data. Linear model relating absolute jacobians on the effects of fat percentage of diet on brain structure in both the offspring at D65 and mothers after weaning was performed. We observed that high fat diets led to extensive changes in the offspring adult brains. Related to NDDs, the strongest effects were seen among structures involved in anxiety, such as amygdala, thalamus, septum, anterior cingulate and basal forebrain. No statistically significant changes were observed in the maternal brains, indicating that the effects of diet are limited to a critical development window.These results underscore that early life is a sensitive period for brain development, as evidenced by the extensive changes caused in the adult brain by exposure to high fat diets during gestation and lactation. The potential link between these changes and the observed higher risk of neurodevelopmental disorders warrants further investigation.