Prefrontal Cortex Dysregulation of Amino Acid-Glucose Homeostasis Links High-Fat and/or High-Fructose Intake to Cognitive Deficits in Male Mice.

Memory processes are susceptible to impairment induced by excessive consumption of hypercaloric diets, particularly those rich in saturated fats and fructose. Such dietary patterns have been linked to disrupted neurotransmission in the prefrontal cortex (PFC), where the balance between excitation and inhibition depends on efficient glucose metabolism and the synthesis of neuroactive amino acids. However, the molecular mechanisms underlying these effects remain poorly understood. Here, male C57BL/6 mice were fed for 10 weeks with a control diet, a high-fat diet (HFD), a high-fructose diet (HFrD), or a combined high-fat/high-fructose diet (HFFrD). Their body weight gain and visceral adiposity were primarily driven by saturated fat intake, whereas hyperglycemia was observed across all diets. Also, we assessed metabolic outcomes, recognition memory, and PFC molecular profiles, including neuroactive amino acids (GABA, glutamate, glutamine, aspartate, alanine, glycine, and taurine) and the expression of genes related to glucose metabolism (Slc2a1, Pcx, G6pd, Gck, Pck1, Irs2) and the glutamate/GABA-glutamine cycle (Glul, Glud1, Gad1, Gad2). Behaviorally, HFFrD reduced locomotor activity and caused the most significant impairment in recognition memory. In the PFC, diet composition generated distinct amino acid profiles, revealing vulnerability of the glutamine-glutamate-GABA cycle to hypercaloric intake. Transcriptional responses were diet-specific, with consistent Gad1 upregulation and broader induction of glucose metabolism-related genes. Together, these findings demonstrate diet-dependent metabolic and neurochemical remodeling in the PFC and support a link between excessive fat and/or fructose intake with disrupted glutamine-glutamate homeostasis and memory deficits.