Prefrontal Cortical Deletion of DNA Methyltransferases Dnmt1 and Dnmt3a Reduces Palatable Food Intake

DNA methylation is an epigenetic mechanism most often associated with the repression of gene expression; mediated by the DNA methyltransferases (DNMT). Expression of both DNMT1 and DNMT3a isoforms within post-mitotic neurons of the central nervous system (CNS) has been shown to be important in modulating the response to drugs of abuse and other stimuli that produce changes in neuronal plasticity. Interestingly, DNMT1 and DNMT3a expression has been shown to be dynamically regulated in the medial prefrontal cortex (mPFC), suggesting that these enzymes may also be involved in the modulation of mPFC dependent behavior. Indeed, obesity induces hypermethylation of the µ-opioid receptor, suggesting that the modulation of methylation may represent an important mechanism engaged to produce changes in PFC function and thus behaviors. Based on these suggestions, we hypothesized that the DNMT enzymes in the PFC act to coordinate palatable food consumption. In a test of this hypothesis, we generated PFC-specific deletions of both the methyltransferases expressed in the CNS, DNMT1 and DNMT3a, and characterized their requirement in feeding behaviors. We demonstrate that animals lacking PFC-specific DNMT1 and DNMT3a showed a significant reduction in palatable food consumption, and that the intake of high-fat food showed less dependence on mPFC methylation state compared to a high fat and high carbohydrate food. Furthermore, the effect on behavior was selective on food intake, with no modulation on other PFC-dependent behaviors. Furthermore, we demonstrate a method to isolate discrete population of neurons from tissue suitable for downstream molecular assays. Our data suggest for the first time that DNA methylation is required for appropriate regulation of palatable food intake.