We previously demonstrated that a high-fat diet (HFD) consumption can cause not only peripheral insulin resistance, but also neuronal insulin resistance. Moreover, the consumption of an HFD has been shown to cause mitochondrial dysfunction in both the skeletal muscle and liver. Rosiglitazone, a peroxisome proliferator-activated receptor-γ ligand, is a drug used to treat type 2 diabetes mellitus. Recent studies suggested that rosiglitazone can improve learning and memory in both human and animal models. However, the effects of rosiglitazone on brain insulin resistance and brain mitochondria after the HFD consumption have not yet been investigated. Therefore, we tested the hypothesis that rosiglitazone improves neuronal insulin resistance caused by a HFD via attenuating the dysfunction of neuronal insulin receptors and brain mitochondria. We found that rosiglitazone (5 mg/kg per day for 14 days) significantly improved peripheral insulin resistance and insulin-induced long-term depression and increased brain Akt/PKB-ser phosphorylation in response to insulin. Furthermore, rosiglitazone prevented brain mitochondrial conformational changes and attenuated brain mitochondrial swelling, brain mitochondrial membrane potential changes, and brain mitochondrial ROS production. Our data suggest that neuronal insulin resistance and the impairment of brain mitochondria caused by a 12-wk HFD consumption can be reversed by rosiglitazone. In addition, the effects of estrogen on the prevention of impaired insulin-induced longterm depression in the hippocampus and brain insulin signaling caused by high-fat diet (HF) were studied in male and female rats. Both male and female rats fed with HF developed peripheral insulin resistance as indicated by increased body weight, visceral fat, plasma insulin and HOMA index. Estrogen administration decreased those parameters, indicating improved peripheral insulin sensitivity, in both male and female HF rats. HF diet consumption also caused impaired insulin-induced long-term depression in hippocampus and impaired brain insulin receptor function and signaling, indicating brain insulin resistance, in both male and female rats. Estrogen treatment could attenuate these brain impairments only in HF female rats. The activation of the estrogen pathway could preserve insulin sensitivity in the peripheral tissue in both male and female rats. In brain, however, the benefit of estrogen could be found only in female rats.