Dietary Fatty Acids Differentially Modulate Hippocampal Glutamate-Related Gene Expression in Mice: Sex-Specific in Vivo and in Vitro Effects.

High-fat diets (HFDs) disrupt hippocampal (HIP) glutamatergic transmission, reducing synaptic plasticity and contributing to cognitive decline. While excessive dietary fat is known to alter glutamate (Glu) homeostasis, the specific effects of saturated versus unsaturated fatty acids and the role of sex remain unclear. We examined two HFDs, one enriched in oleic acid (OA) (UOLF, unsaturated) and another in palmitic and lauric acids (LAs) (SOLF, saturated), in young adult male and female mice. In males, both diets increased HIP Glu and glutamine (Gln) levels; however, only UOLF upregulated genes linked to Glu/Gln uptake and synthesis, suggesting an adaptive metabolic response. These changes were absent in females, indicating marked sex-dependent effects. In cultured HIP neurons and astrocytes, OA caused milder alterations than palmitic acid (PA) and selectively activated pathways that may lower extracellular Glu and enhance recycling. Lauric acid (LA) failed to activate protective mechanisms, implying it is a major driver of HIP dysfunction in males consuming saturated fats. Both diets disrupted the HIP Glu-Gln cycle in males, but only unsaturated fats triggered compensatory mechanisms that mitigate Glu accumulation. These findings emphasize the critical role of dietary fat composition and biological sex in shaping HIP Glu metabolism and glutamatergic function.