The effects of the consumption of high-fat diets (HFD) have been studied to unravel the molecular pathways they are altering in order to understand the link between increased caloric intake, metabolic diseases, and the risk of cognitive dysfunction. The saturated fatty acid, palmitic acid (PA), is the main component of HFD and it has been found increased in the circulation of obese and diabetic people. In the central nervous system, PA has been associated with in ammatory responses in astrocytes, but the effects on neurons exposed to it have not been largely investigated. Given that PA affect a variety of metabolic pathways, we aimed to analyze the transcriptomic pro le activated by this fatty acid to shed light on the mechanisms of neuronal dysfunction. In the current study, we pro led the transcriptome response after PA exposition at non-toxic doses in primary hippocampal neurons. Gene ontology and Reactome pathway analysis revealed a pattern of gene expression which is associated with in ammatory pathways, and importantly, with the activation of lipid metabolism that is considered not very active in neurons. Validation by qRT-PCR of Hmgcs2, Angptl4, Ugt8 and Rnf145 support the results obtained by RNAsEq. Overall, these ndings suggest that neurons are able to respond to saturated fatty acids changing the expression pattern of genes associated with in ammatory response and lipid utilization that may be involved in the neuronal damage associated with metabolic diseases.