Figure 1. The hypothalamic melanocortin system. ARC POMC neurons produce aMSH and other POMC-derived peptides that act on downstream MC4R-expressing cells, such as PVH MC4R cells that play crucial roles in the suppression of food intake. ARC AgRP neurons (which also contain the inhibitory neurotransmitters NPY and GABA) release AgRP to antagonize MC4R signaling (increasing food intake) and also inhibit other PVH neurons to increase food intake and decrease energy expenditure. Signals of energy surfeit (including leptin) promote POMC neuron action; serotonin (5HT) also promotes POMC neuron action via 5HTR2c on these cells. In contrast, leptin inhibits AgRP cells, while orexigenic ghrelin also activates them. Not only does leptin act directly on these cells, but leptin action on unidentified LepRb/GABA neurons represents a major modulator of the melanocortin system.