Chronic consumption of high fat diets (HFD) is a risk factor for the development of metabolic diseases such as obesity and diabetes, and it is also associated with cognitive impairment and Alzheimer´s disease. Palmitic acid (PA) is a major component of HFD, and high concentrations of this saturated fatty acid exerts pleiotropic actions in cells. The PA effects have been largely studied in peripheral tissues where is considered a driving force for the development of many metabolic diseases such as obesity, insulin resistance and Type II diabetes. In the brain, particularly in neurons, it is able to increase oxidative metabolism, induce insulin resistance, and alter gene expression. However, little is known about how PA-induced metabolic alterations may affect gene expression mechanisms in neurons. One of the most studied PA-dependent mechanisms is associated with the lipid-induced activation of the transcription factors, PPAR-γ and PGC-α, but fewer studies have analyzed the PA-dependent regulation of epigenetic mechanisms. In this study, we identified PA-linked changes in the class I histone deacetylases (HDACs) content associated with chromatin acetylation and with differential expression of the BDNF-encoding gene and the non-coding retrotransposon, LINE1 in differentiated human neuroblastoma cells.