Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance

The hormones ghrelin and leptin act via the lateral hypothalamic area (LHA) to modify energy balance, but the underlying neural mechanisms remain unclear. We investigated how leptin and ghrelin engage LHA neurons to modify energy balance behaviors and whether there is any crosstalk between leptin and ghrelin-responsive circuits. We demonstrate that ghrelin activates LHA neurons expressing hypocretin/orexin (OX) to increase food intake. Leptin mediates anorectic actions via separate neurons expressing the long form of the leptin receptor (LepRb), many of which coexpress the neuropeptide neurotensin (Nts); we refer to these as Nts(LepRb) neurons. Because Nts(LepRb) neurons inhibit OX neurons, we hypothesized that disruption of the Nts(LepRb) neuronal circuit would impair both Nts(LepRb) and OX neurons from responding to their respective hormonal cues, thus compromising adaptive energy balance. Indeed, mice with developmental deletion of LepRb specifically from Nts(LepRb) neurons exhibit blunted adaptive responses to leptin and ghrelin that discoordinate the mesolimbic dopamine system and ingestive and locomotor behaviors, leading to weight gain. Collectively, these data reveal a crucial role for LepRb in the proper formation of LHA circuits, and that Nts(LepRb) neurons are important neuronal hubs within the LHA for hormone-mediated control of ingestive and locomotor behaviors.