Over the past several decades, the prevalence rates of obesity have reached epidemic levels. Dietary factors are important predictors of the general health of individuals; however, the actual impact of diet on brain structure and function remains poorly understood. Physical exercise has been shown to improve psychological and cognitive function in humans and mice, so that, our objective are to evaluate the effect that high fat diet (HF) and spontaneous physical exercise have in peripheral tissue and hippocampus. Mice CF1 were divided into four groups: low fat sedentary (LFS), low fat exercise (LFE), high fat sedentary (HFS) and high fat exercise (HFE) during five months. After that, animals were decapitated, blood collected and centrifuged and fat tissue, liver and hippocampus rapidly dissected and kept in -80ºC. We evaluated HDL, LDL, cholesterol and tryacilgycerol (TAG) in blood. In liver we evaluated intracellular TAG and, in hippocampus, the phosphorylation state of ERK1/2 (pERK1/2) and CREB (pCREB). Data were analyzed using two-way ANOVA and Test-t Student. Our results demonstrated that, surprisingly, LFE has increased blood TAG levels when compared to the others groups studied, but HFS has increased levels of TAG (p<0,05) in the liver. HFS showed increased abdominal fat pad weights (p<0,05) than the other groups. The groups that exercised for 5 months showed a tendency to increase pERK1/2 (p=0,09) and pCREB (p=0,052). Our results also demonstrated that HF without exercise impaired liver function because high TAG in the liver and abdominal obesity are markers of insulin resistance. Exercise reverses the harmful effects of HF in these parameters. In hippocampus, HF had no effect in pERK1/2 and pCREB. These data do not agree with other studies showing an alteration in the phosphorylation state of the above mentioned proteins in consequence of a HF. Our results could be due to the long exposure of the animals to the diet and could reflect an adaptative response of the brain to the long HF. The tendency to increase pERK1/2 and pCREB observed in the exercised groups could explain why an improvement in cognition and memory is usually associated with physical activity.