It is now established that the hypothalamus is essential in coordinating endocrine, autonomic, and behavioral responses to changes in energy availability. However, the interaction between key neuropeptides and neurotransmitters systems within the hypothalamus has yet to be delineated. Recently, we investigated the mechanisms through which central serotonergic (5-hydroxytryptamine, 5-HT) systems recruit leptin-responsive hypothalamic pathways, such as the melanocortin systems, to affect energy balance. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we found that 5-HT drugs require functional melanocortin pathways to exert their effects on food intake.

Specifically, we observed that anorectic 5-HT drugs activate proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (Fig. 1).

We provide evidence that the serotonin 2C receptor (5-HT2CR) is expressed on POMC neurons and contributes to this effect (Fig. 2).

Finally, we found that 5-HT drug-induced hypophagia is attenuated by pharmacological or genetic blockade of downstream melanocortin 3 and 4 receptors (Fig. 3).

A model is presented in which activation of the melanocortin system is downstream of 5-HT and is necessary to produce the complete anorectic effect of 5-HT drugs. These data incorporate the central 5-HT system to the growing list of metabolic signals that converge on melanocortin neurons in the hypothalamus.

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