Leptin Action via Neurotensin Neurons Controls Orexin, the Mesolimbic Dopamine System and Energy Balance

Leptin acts on leptin receptor (LepRb)-expressing neurons throughout the brain, but the roles for many populations of LepRb neurons in modulating energy balance and behavior remain unclear. We found that the majority of LepRb neurons in the lateral hypothalamic area (LHA) contain neurotensin (Nts). To investigate the physiologic role for leptin action via these LepRbNts neurons, we generated mice null for LepRb specifically in Nts neurons (Nts-LepRbKO mice). Nts-LepRbKO mice demonstrate early-onset obesity, modestly increased feeding, and decreased locomotor activity. Furthermore, consistent with the connection of LepRbNts neurons with local orexin (OX) neurons and the ventral tegmental area (VTA), Nts-LepRbKO mice exhibit altered regulation of OX neurons and the mesolimbic DA system. Thus, LHA LepRbNts neurons mediate physiologic leptin action on OX neurons and the mesolimbic DA system, and contribute importantly to the control of energy balance. ► Neurotensin identifies a circumscribed subpopulation of LepRb neurons (LepRbNts) ► Loss of leptin signaling in LepRbNts neurons of Nts-LepRbKO mice results in obesity ► OX neurons and the mesolimbic DA system are dysregulated in Nts-LepRbKO mice ► Leptin controls OX, mesolimbic DA, and energy balance via LepRbNts neurons