Obesity-associated memory impairment and neuroinflammation precede widespread peripheral perturbations in aged rats

Background: Obesity and metabolic syndrome are major public health concerns linked to cognitive decline with aging. Prior work from our lab has demonstrated that short-term high fat diet (HFD) rapidly impairs memory function via a neuroinflammatory mechanism. However, the degree to which these rapid inflammatory changes are unique to the brain is unknown. Moreover, deviations in gut microbiome composition have been associated with obesity and cognitive impairment, but how diet and aging interact to impact the gut microbiome, or how rapidly these changes occur, is less clear. Thus, our study investigated the impact of HFD after two distinct consumption durations: 3 months (to model diet-induced obesity) or 3 days (to detect the rapid changes occurring with HFD) on memory function, anxiety-like behavior, central and peripheral inflammation, and gut microbiome profile in young and aged rats. Results: Our data indicated that both short-term and long-term HFD consumption impaired memory function and increased anxiety-like behavior in aged, but not young adult, rats. These behavioral changes were accompanied by pro- and anti-inflammatory cytokine dysregulation in the hippocampus and amygdala of aged HFD-fed rats at both time points. However, changes to fasting glucose, insulin, and inflammation in peripheral tissues such as the distal colon and visceral adipose tissue were increased in young and aged rats only after long-term, but not short-term, HFD consumption. Furthermore, while subtle HFD-induced changes to the gut microbiome did occur rapidly, robust age-specific effects were only present following long-term HFD consumption. Conclusions: Overall, these data suggest that HFD-evoked neuroinflammation, memory impairment, and anxiety-like behavior in aging develop quicker than, and separately from the peripheral hallmarks of diet-induced obesity.