Prolonged Early Exposure to a High-Fat Diet Augments the Adverse Effects on Neurobehavior and Hippocampal Neuroplasticity: Involvement of Microglial Insulin Signaling.

High-fat diet (HFD) consumption may contribute to the high prevalence of cognitive-emotional issues in modern society. Mice fed a HFD for a prolonged period develop more severe neurobehavioral disturbances when first exposed to a HFD in the juvenile period than in adulthood, suggesting an initial age-related difference in the detrimental effects of long-term HFD feeding. However, the mechanism underlying this difference remains unclear. Here, male C57BL/6J mice initially aged 4 (IA4W) or 8 (IA8W) weeks were fed a control diet (CD) or HFD for 6 months and then subjected to metabolic, neurobehavioral, and histomorphological examinations. Although the detrimental effects of long-term HFD feeding on metabolism and neurobehavior were observed in mice of both ages, IA4W-HFD mice showed significant cognitive inflexibility accompanied by significantly greater levels of anxiety-like behavior than age-matched controls. Hippocampal neuroplasticity and microglial phenotype were altered by HFD feeding, whereas significant morphological alterations were more frequently observed in IA4W-HFD mice than in IA8W-HFD mice. Additionally, significantly increased hippocampal microglial engulfment of postsynaptic proteins and elevated phospho-insulin-receptor levels were observed in IA4W-HFD, but not in IA8W-HFD, mice. These findings suggest that aberrant microglia-related histomorphological changes in the hippocampus underlie the exacerbated detrimental neurobehavioral effects of prolonged early HFD exposure and indicate that enhanced insulin signaling might drive microglial dysfunction after prolonged early HFD exposure.