The present study aims to determine if age-dependent obesity resulting from HF diet feeding causes IR in the periphery, affects insulin signaling in the hippocampus, leads to impaired age-related behavioral and memory changes, and worsens neuroinflammation in the brain separately in males and females of THY-Tau22 mice and corresponding wild-type (wt) controls. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.