Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Summary The nucleus of the solitary tract (NTS) is emerging as a major site of action for the appetite-suppressive effects of leading pharmacotherapies currently investigated for the treatment of obesity. However, our understanding of how NTS neurons regulate appetite remains incomplete. Here we used NTS nutrient sensing as an entry point to characterize stimulus-defined neuronal ensembles engaged by the NTS to produce physiological satiety. Using activity-dependent expression of genetically-encoded circuit analysis tools, we found that NTS detection of leucine engages NTS prolactin-releasing peptide (PrRP) neurons to inhibit AgRP neurons via a population of leptin-receptor-expressing neurons in the dorsomedial hypothalamus. This circuit is necessary for the anorectic response to NTS leucine, the appetite-suppressive effect of high protein diets, and the long-term control of energy balance. These results extends the integrative capability of AgRP neurons to include brainstem nutrient sensing inputs.