The proopiomelanocortin (POMC) system plays an important role in regulating energy homeostasis, in part, through action of the POMC-derived peptide alpha-MSH on the neuroanatomically distributed melanocortin 3/4-receptor (MC3/4R). While food intake control circuits deriving from hypothalamic POMC neurons have been well investigated, the mechanism by which POMC neurons of the nucleus tractus solitarius (NTS) suppress feeding behavior remains unknown. Here, we demonstrate NTS POMC projections to the mesencephalic trigeminal nucleus (MeV), a CNS ganglion involved in the processing of orosensory information and the control of oral motor output.
Mice were used for all experiments. Projections from NTS POMC neurons to the MeV were confirmed using the retrograde tracer Fluorogold in combination with viral labeling of NTS POMC neurons. Fluorescent in situ hybridization (FISH) was next used to identify expression of the MC4R on neuronal cell bodies of the MeV. Food intake and body weight changes following pharmacological activation of MeV MC3/4Rs was next demonstrated using the MC3/4-R agonist melanotan-II (MTII). Lastly, the functional relevance of the NTS POMC to MeV projection was analyzed using a Cre-dependent excitatory adeno-associated DREADD virus injected into the NTS of POMC-Cre mice to allow for selective stimulation of NTS POMC neurons with clozapine-N-oxide (CNO).
We observed projections from NTS POMC neurons to the MeV. The MeV expresses MC4Rs, as demonstrated by our FISH work, which when activated via MTII, suppresses food intake and body weight. Lastly, delivery of CNO directly to the POMC neuron terminals in the MeV recapitulates the anorectic effects of systemic CNO delivery.
Our work provides evidence that NTS POMC neurons project to the MeV and that MC4Rs in the MeV are sufficient for the suppression of feeding behavior. Future studies are aimed at exploring the role of the MeV MC3/4R in the modulation of satiety via control of oral motor outputs.