Small-litter and cafeteria diet (CAF) models are useful tools to study obesity at experimental level. Our objective was to assess the effects of neonatal overfeeding (NO) and adult exposure to CAF on the brain homeostatic system that regulates food intake. Male Wistar rats were raised in small (4 pups/dam, SL) or normal litters (10 pups/dam, NL), from weaning to postnatal day (PND) 90 they were fed a control diet (CON). Then, animals received CON or CAF (NL-CON, NL-CAF, SL-CON, SL-CAF; 12±2 rats/group) for 11 weeks. Food intake, body weight and naso anal length were measured weekly until brain collection at the end of the experiment. Arcuate nucleus (ARC) was isolated by micro-punch technique, RT-qPCR was conducted to assess the expression of Agouti-related protein (AgRP), Neuropeptide Y (NPY), Cocaine- and amphetamine-regulated transcript (CART), Proopiomelanocortin (POMC), insulin (IR), ghrelin (GHSR) and leptin (ObRb) receptors. Neonatal overfeeding and CAF diet increase Body Mass Index and alter dietary preferences. At transcriptional level, early overnutrition impaired hypothalamic Pomc expression in ARC through an epigenetic mechanism. On the other hand, NPY expression is decreased by neonatal overnutrition, apparently responding to peripheral stimuli. Leptin receptor expression is reduced because of the CAF diet. These findings show that events experienced during early life program lasting alterations in the response to an unhealthy diet in adulthood.