p53 is a transcriptional factor modulating numerous biological actions. Although it is best known for its role in cancer development, it is now evident that it is implicated in metabolism. More specifically, p53 modulates energy metabolism and homeostasis through their effects on adipocyte development and function. However, nothing is known about the potential metabolic function of p53 in the central nervous system.Neuronal networks within the central nervous system play a crucial role in the regulation of food intake, body weight, and glucose homeostasis, so the main objective of this project will be to evaluate the potential of brain p53 as anti-obesity and/or anti-diabetic drug candidate. Our project will dissect precisely which specific components of energy balance are altered after central disruption or rescue of p53 signalling in selective neuronal populations, as well as the molecular pathways mediating these actions.More precisely, we will disrupt the central p53 signalling specifically in hypothalamic POMC and AgRP neurons, which are crucial for energy and glucose homeostasis. We will also generate and characterize mice lacking p53 in dopamine neurons that are essential for mechanisms related with the reward of food. Once we know which specific areas are crucial for the central actions of p53, we will complete the experiments rescuing p53 expression in selective neuronal populations (POMC, AgRP or dopamine neurons) of p53 null mice. We will also investigate the interaction between p53 with leptin and ghrelin, likely the two more important hormones in the regulation of energy balance, which act through homeostatic and hedonic mechanisms. Understanding the precise role and mechanisms regulated by central p53 on energy balance may open new avenues for the identification of potential anti-obesity drug targets directed towards specific molecular pathways.