Obesity is an epidemic disease that may affect brain function. The present study examined the effect of high fat diet (HF) and physical exercise on peripheral tissue and hippocampal signaling. CF-1 mice (n = 4, per cage) were divided into groups receiving high fat (HF) or control (CD) diets for 5 months, with or without voluntary exercise. Serum triacylglycerol, total cholesterol, HDLc, liver triacylglycerol and glycogen concentrations were evaluated (n = 6). Also, the phosphorylation state of the AKT --> ERK 1/2 --> CREB pathway (AKT, pAKTser473, ERK 1/2, pERK 1/2, CREB and pCREB, n = 4-6) was analyzed in the hippocampus. HF diet caused an increase in AKT phosphorylation at ser473 (P < 0.05), while exercise increased the phosphorylation of ERK 1/2 (P < 0.05) and CREB (P < 0.05). As expected, exercise reversed some of the harmful effects of HF, i.e., increased liver deposition of fat (P < 0.05) and fat gain in the abdominal region (P < 0.05). In conclusion, the effects of exercise and HF diet on brain signaling appear to affect the hippocampal AKT --> ERK 1/2 --> CREB pathway in independent ways: HF intake caused increased phosphorylation of AKTser473, while exercise increased ERK 1/2 --> CREB signaling. The physiological relevance of these findings in brain function remains to be elucidated.