The hypothalamus is one of the key areas in the regulation of energy homeostasis as it receives constant updates on metabolic state from the periphery, it integrates this information and ultimately initiates necessary adjustments. Although tremendous progress in understanding the hypothalamic pathways regulating metabolic balance has been made in recent years, much of the information on how hypothalamic neurons sense nutrient state and translate that information into adjustment of neuronal function and ultimately e.g. food intake remains poorly understood. Here, we will briefly review some of the current state-of-the-art in our knowledge of the hypothalamic pathways regulating energy homeostasis, but then focus on our use of hypothalamic nutrient-sensing as a model in which to study the interplay between a neuron’s dynamically modified transcriptional state and it’s physiological function. We have identified an important role for the CREB co-activator CRTC2 (CREB-regulated transcription co-activator) in linking hypothalamic glucose-sensing to appropriate CREB-target gene expression (1). Using hypothalamic area-specific genetically modified mice we demonstrate that hypothalamic CRTC2 indeed links glucose-sensing with an appropriate transcriptome which ultimately regulates food intake.