The incidence of obesity is closely associated with the increased intake of saturated fat and sugar-sweetened beverages, however the mechanisms that regulate the consumption of dietary fat and sugared beverages remain to be determined. We used a novel animal model of obesity that closely resembles the consumption pattern observed in humans, characterized by the abundance of readily available food items containing saturated fat and sugar. In this model, animals are provided with the choice for a fat and sugar component, in addition to a regular nutritionally balanced pellet food and water. This unique animal model with free-choice diets is not only an effective model of diet-induced obesity, but it also characterizes the snacking behavior, increased motivation and alterations in metabolic parameters that closely resemble human obesity and the metabolic syndrome. In this thesis, we show that the composition of the diet, and not the fat mass per se, is important for how the brain responds to diet-induced obesity and subsequently regulates feeding behavior. We found that especially the combination of fat and sugar (and not fat or sugar alone) leads to obesity, insensitivity to the satiety hormone leptin and increased sensitivity for the hunger peptide Neuropeptide Y (NPY). Moreover, we revealed a novel role of NPY in the brain reward center (nucleus accumbens) in the regulation of fat intake, and showed novel anatomical connections of NPY to the nucleus accumbens and how NPY in the nucleus accumbens decreases neuronal activity, leading to increased fat intake. Together, these data lead to a better understanding how the combination of fat and sugar alters certain brain regions and how these changes contribute to chronic overeating and development of obesity.