In this study, we investigated the neurochemical alterations in mouse hippocampus using in vivo proton magnetic resonance spectroscopy. We also examine the effect of high-fat diet on the levels of abdominal fat, plasma leptin, and corticosterone. The decrease in mIns concentration seen in HF diet mice without corresponding Gln-Glu alternation may reflect changes in glial function. In addition, the observed total choline levels indicate attenuated membrane turnover in HF diet mice. We therefore suggest that diets rich in saturated fats induce a stress-related response through metabolic disturbance and HPA axis dysfunction, which may indicate a relationship between obesity and depression.