How do dynamically modulated neuronal transcriptomes underpin long-term adaptive changes that lead to positive processes, such as learning, or negative adaptations, like failure to sense metabolic state? This is a core question in neurobiology and ultimately CNS-mediated disease and my lab is using hypothalamic nutrient-sensing as a model to investigate the programmes supporting such neuronal plasticity. Hypothalamic nutrient-sensing is critical for maintenance of appropriate body weight and glucose homeostasis. However, in clinical situations such as obesity and type 2 diabetes, but also recurrent hypoglycemia in type 1 diabetes, hypothalamic nutrient-sensing fails and adjustment of metabolic balance is lost. In addition to a continued rise in obesity and diabetes in an adult population, early life events are major determinants of obesity and diabetes risk with in utero exposure being of particular importance. With an increasing number of obese, diabetic mothers, maternal programming of offspring metabolic homeostasis adds momentum to the ‘obesity epidemic’. Our recent data investigate the neuroadaptive mechanisms underpinning neuronal responses to metabolic state. Indeed, many neuroadaptative responses are downstream of the induction of transcription factors and subsequent regulation of gene expression, which can have long-lasting effects on neuronal function. We have recently described a mechanism linking hypothalamic glucose-sensing with CRE-gene transcription via activation of a CREB co-activator and linked the subsequently induced transcriptome to the regulation of food intake. In addition, we demonstrate that maternal diet has significant effects on offspring hypothalamic transcriptome regulation and subsequently metabolic balance. By combining the use of neuronal subpopulation-specific genetically modified mouse models with genome-wide transcriptomics and epigenomics approaches we are in the process of identifying mechanisms in environmental- and disease-mediated modifications of neuronal transcriptomes causing neuronal dysfunction.