Major Depressive Disorder (MDD) is a high-prevalence neuropsychiatric condition characterized by depressed mood and anxiety. The risk of suffering MDD is higher in people with obesity and metabolic dysregulation. We will evaluate the effect of a high-fat diet (HFD) and the impact of gender on behavioural, neurochemical and molecular markers associated with depression/anxiety.Male and female C57BL/6 mice, 6-weeks old, were given a 7-week HFD (60% fat). The behavioural tests performed were: open field test (OFT), novelty-suppressed feeding (NSF) test, sucrose preference test (SPT), and tail suspension test (TST). Neurochemical analysis was performed by HPLC in the hippocampus and prefrontal cortex. Plasticity and inflammatory markers were evaluated using western blot and ELISA in the hippocampus and plasma, respectively.HFD mice showed an anxious-like phenotype by an increased latency to feed in the NSF (p<0.001) and reduction of the central time in the OFT, both male (p<0.05) and female (p<0.001) mice. Only female mice presented increased despair in the TST (p<0.05) and anhedonia in the SPT (p<0.01) indicating a depressive-like behaviour. Reduced mTOR pathway activation was observed in the male HFD hippocampus (p<0.05). Finally, IL-6 plasma levels were lower in female HFD mice (p<0.05), whereas IL-10 was lower in both male (p<0.05) and female (p<0.01) HFD mice. HFD regulates differentially the hippocampal kynurenine levels in both genders.Our results confirm the interplay between anxiety/depression and a HFD, showing a sexual dimorphism in behaviour and the mechanisms involved. Nevertheless, further investigation is needed to understand the molecular processes underlying obesity and depression.