Body weight is determined by feeding and volitional physical activity behaviors that are regulated, in part, by dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we sought to understand how the neuropeptide, neurotensin (Nts) engages VTA DA neurons to modify body weight. The rationale for this work is that pharmacologic application of Nts into the VTA suppresses food intake and promotes locomotor activity, yet the endogenous circuits by which Nts acts on the VTA to modify these... Show moreBody weight is determined by feeding and volitional physical activity behaviors that are regulated, in part, by dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we sought to understand how the neuropeptide, neurotensin (Nts) engages VTA DA neurons to modify body weight. The rationale for this work is that pharmacologic application of Nts into the VTA suppresses food intake and promotes locomotor activity, yet the endogenous circuits by which Nts acts on the VTA to modify these behaviors and body weight remain unclear. First, we identified the endogenous sources of Nts input to the VTA; using retrograde tracing we found that the lateral hypothalamic area (LHA), a critical neural hub for coordinating energy balance, provides substantial Nts projections to the VTA. We next examined how Nts directly engages VTA DA neurons by identifying Nts receptor-expressing cells in the VTA. To do this, we generated mice expressing Cre-recombinase in Nts receptor 1 (NtsR1) or Nts receptor 2 (NtsR2) cells, which revealed that NtsR1 is expressed on many VTA DA neurons, whereas NtsR2 is predominantly restricted to glial cells. Furthermore, only the VTA NtsR1 neurons project to the nucleus accumbens (NA), where DA release is known to modify feeding and locomotor behavior. We therefore tested the physiologic necessity for Nts action via the VTA by genetically ablating VTA NtsR1 neurons. Mice lacking VTA NtsR1-DA neurons were hyperactive, failed to gain weight, and could not appropriately coordinate feeding behavior with peripheral energy cues, demonstrating that VTA NtsR1 neurons are essential for energy balance. Finally, we tested the hypothesis that endogenous Nts input from the LHA to the mesolimbic DA system would be sufficient to regulate body weight. Indeed, chemogenetic activation of LHA Nts neurons increased physical activity, restrained food intake, and promoted weight loss in lean mice. Interestingly, the anorectic effects of LHA Nts activation were mediated via NtsR1 and DA signaling, while the physical activity was NtsR1-independent. Furthermore, in hungry mice (a state in which increased appetitive drive can promote overeating and weight gain), activation of LHA Nts neurons suppressed intake of chow and palatable sucrose rewards. Collectively, this work defines an endogenous LHA Nts circuit that engages the mesolimbic DA system via NtsR1 to suppress food intake in both energy replete and energy depleted states. Enhancing action via this circuit may thus be useful to support dual weight loss behaviors in an obesogenic environment. Show less
