Lateral septum as a melanocortin downstream site in obesity development

The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that mediate its action are not clear. Here, we found that, among the known paraventricular hypothalamic (PVH) neuron groups, those expressing melanocortin receptors 4 (PVH^Mc4R) preferably project to the ventral part of the lateral septum (LSv), a brain region known to be involved in emotional behaviors. Photostimulation of PVH^Mc4R neuron terminals in the LSv reduces feeding and causes aversion, whereas deletion of Mc4Rs or disruption of glutamate release from LSv-projecting PVH neurons causes obesity. In addition, disruption of AMPA receptor function in PVH-projected LSv neurons causes obesity. Importantly, chronic inhibition of PVH- or PVH^Mc4R-projected LSv neurons causes obesity associated with reduced energy expenditure. Thus, the LSv functions as an important node in mediating melanocortin action on body-weight regulation.