Obesity and excessive consumption of saturated fats represent important predisposing factors to the development of neurodegenerative disorders such as Alzheimer's disease (AD) and its neuropsychiatric comorbidities. Alteration of amyloid β (Aβ) homeostasis is considered the main neuropathological feature of AD and increased levels of the oligomeric forms of this peptide have been associated with increased risk of depressive states. The exposure to obesogenic environment, such as high fat diet (HFD), seems to impair Aβ catabolic function leading to the production of its neurotoxic species. In the present work, by using a behavioral and molecular approach, we evaluated in mice, both male and female, the effect of long-life exposure to HFD from preconceptional period until early life (8 weeks of age). We found that only male HFD fed mice showed a depressive-like phenotype in the tail suspension test and an anxiety-like phenotype in the elevated plus maze test. However, at peripheral level we found a significant reduction in serotonin levels accompanied by increased kynurenine and 3-Hydroxykynurenine (3-HKYN) content. On the other hands, in the prefrontal cortex (PFC) and in the hippocampus of HFD groups only the neuorinflammatory 3-HKYN was increased. In PFC, we found enhanced amount of Aβ oligomeric species and reduced BDNF content.Therefore, our data suggest that the difference between the periphery and the center may indicate that depressive-like phenomenon induced by HFD exposure is associated with alterations initially established at peripheral level and subsequently affecting the brain, by accumulating neurotoxic amyloid species.