POMC-derived
melanocortins inhibit food intake. In the adult rodent brain,
POMC-expressing neurons are located in the arcuate nucleus (
ARC) and the nucleus tractus solitarius (NTS), but it remains unclear how
POMC neurons in these two brain nuclei regulate feeding behavior and metabolism differentially. Using pharmacogenetic methods to activate or deplete neuron groups in separate brain areas, in the present study, we show that
POMC neurons in the
ARC and NTS suppress feeding behavior at different time scales. Neurons were activated using the DREADD (designer receptors exclusively activated by
designer drugs) method. The evolved human M3-muscarinic receptor was expressed in a selective population of
POMC neurons by stereotaxic infusion of
Cre-recombinase-dependent, adeno-associated virus vectors into the
ARC or NTS of
POMC-Cre mice. After injection of the human M3-muscarinic receptor
ligand clozapine-N-oxide (1 mg/kg, i.p.), acute activation of NTS
POMC neurons produced an immediate inhibition of feeding behavior. In contrast, chronic stimulation was required for
ARC POMC neurons to suppress food intake. Using adeno-associated virus delivery of the
diphtheria toxin receptor gene, we found that
diphtheria toxin-induced ablation of
POMC neurons in the
ARC but not the NTS, increased food intake, reduced energy expenditure, and ultimately resulted in
obesity and metabolic and endocrine disorders. Our results reveal different behavioral functions of
POMC neurons in the
ARC and NTS, suggesting that
POMC neurons regulate feeding and energy homeostasis by integrating long-term adiposity signals from the hypothalamus and short-term satiety signals from the brainstem.