(a) Multiple peripheral factors have been shown to modify food intake and energy expenditure through direct effects on the CNS. (b) Evidence suggests that melanocortin signaling regulates these physiological processes by means of distinct projection patterns originating from POMC neurons in the arcuate nucleus (Arc). Ultimately, MC4 receptor (MC4R)-expressing neurons downstream of POMC neurons act to suppress food intake and increase energy expenditure. Hypothalamic NPY/AgRP, paraventricular nucleus of the hypothalamus (PVH) and VMH neurons, as well as hindbrain DVC, parabrachial nucleus (PBN) and spinal cord intermediolateral cell column (IML) neurons, also regulate or counter-regulate these activities. PP, pancreatic polypeptide; PYY, peptide YY; 3V, third ventricle.