Effects of metabolic state on the regulation of melanocortin circuits

•The melanocortin system is conserved across species and an important regulator of metabolism.•Melanocortin neurons have diverse projections and heterogenous molecular profiles.•The melanocortin circuit rapidly adapts to metabolic signals/challenges and energy state.•Exercise (during and after) exerts opposing effects on POMC and NPY/AgRP neurons.•Defining flexibility of relevant neural circuits may advance therapeutics of metabolic disease. Dysfunction in neurophysiological systems that regulate food intake and metabolism are at least partly responsible for obesity and related comorbidities. An important component of this process is the hypothalamic melanocortin system, where an imbalance can result in severe obesity and deficits in glucose metabolism. Exercise offers many health benefits related to cardiovascular improvements, hunger control, and blood glucose homeostasis. However, the molecular mechanism underlying the exercise-induced improvements to the melanocortin system remain undefined. Here, we review the role of the melanocortin system to sense hormonal, nutrient, and neuronal signals of energy status. This information is then relayed onto secondary neurons in order to regulate physiological parameters, which promote proper energy and glucose balance. We also provide an overview on the effects of physical exercise to induce biophysical changes in the melanocortin circuit which may regulate food intake, glucose metabolism and improve overall metabolic health.