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The central melanocortin system plays a critical role in the regulation of energy balance in rodents and humans. The melanocortin signals in both the hypothalamus and brainstem contribute to this regulation. However, how the melanocortin signals of the hypothalamus interact with those intrinsic to the brainstem in the regulation of energy balance is poorly understood. The brainstem raphe pallidus (RPa) and adjacent areas contain melanocortin 4 receptor (MC4-R)-bearing neurons and sympathetic premotor neurons regulating thermogenesis. Here we report that α-melanocyte-stimulating hormone (α-MSH)-immunoreactive (IR) fibers are in close apposition to MC4-R neurons in the RPa. Retrograde tracing studies revealed a unique direct projection from hypothalamic proopiomelanocortin (POMC) neurons to the RPa and adjacent areas of the brainstem in mice and rats. Furthermore, microinjection of the MC3/4-R agonist MTII into the RPa area dose-dependently stimulated oxygen consumption and inhibited feeding, whereas microinjection of the antagonist, SHU9119, enhanced feeding. These data suggest a novel pathway of hypothalamic POMC neuronal efferents to brainstem RPa area MC4-R neurons in the melanocortin circuitry that contribute to coordinate regulation of energy balance.