Transcriptomic Changes in the Frontal Cortex of Juvenile Pigs with Diet-Induced Metabolic Dysfunction-Associated Liver Disease.

: Neurodegenerative disorders have a complex multifactorial pathogenesis that develop decades before the initial symptoms occur. One of the crucial factors in the development of neurodegenerative disorders is an unbalanced diet. A pediatric animal model of diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD) was established by feeding juvenile Iberian pigs a diet high in fat and fructose for 10 weeks. The aim of this study was to investigate the initial molecular imbalances in the frontal cortex (FC) of diet-induced juvenile MASLD pig model and determine whether these changes are associated with neuronal loss. : Eighteen 15-day-old Iberian pigs were randomly assigned to either a standard diet (SD) or a Western diet (WD) for 10 weeks. A short-term recognition memory test and animal activity was recorded during the study. Animals were euthanized in week 10, and the FC and hippocampus (HIP) tissue samples were collected for immunohistochemistry and transcriptomics analyses. : WD-fed pigs developed MASLD. There were no significant differences in animals' activity or recognition memory between WD and SD. To identify and quantify mature neurons, NeuN immunostaining intensity was measured, which was significantly lower in the FC of WD than SD ( ≤ 0.05), but it did not change in HIP ( ≥ 0.05). The Wnt/β-catenin pathway, which promotes neuronal survival and neurogenesis, was downregulated in FC of WD-fed pigs ( ≤ 0.05). Similarly, cytoskeleton organization and extracellular matrix biological processes were downregulated in FC of WD-fed pigs ( ≤ 0.05), whereas the mitochondrial respiratory chain complex and mitochondrion increased in FC of WD compared with SD ( ≤ 0.01). There were several other significantly modulated pathways including signal transduction, cell migration, axon guidance, and calcium ion binding. : The high-fructose, high-fat diet led to neuronal loss in the frontal cortex of MASLD pigs and dysregulated gene expression of the Wnt/β-catenin signaling pathway, cytoskeleton organization, extracellular matrix, and mitochondrial respiratory chain-all pathways that are found deregulated in neurodegnerative diseases.