Peripherally delivered glucagon-like peptide-1 (GLP-1)-based drugs suppress eating through their action in the brain. However, the specific neuronal mechanisms, especially their impacts on the orexigenic circuit, remain largely elusive. Neuropeptide Y (NPY) neurons in the nucleus tractus solitarius (NTS) are newly identified as orexigenic neurons with a potent eating-stimulating effect, but their responses to GLP-1 drugs are unknown. Through ex vivo electrophysiological recordings, we study the impacts of GLP-1 receptor (GLP-1R) agonist exendin-4 on NTSneurons. We discovered that the GLP-1R agonist exendin-4 inhibits NTSneuronal activity via GABAreceptors by augmenting presynaptic GABA release. We also explored the contribution of NTSneurons to exendin-4-mediated eating suppression. Interestingly, chemogenetic activation of NTSneurons effectively counteracted exendin-4-induced anorexigenic effect. Moreover, chemogenetic inhibition of NTSneurons mimicked the eating-suppressing effect of exendin-4. Collectively, our findings highlight a population of orexigenic NTSneurons that may be targeted by a GLP-1R agonist to suppress food intake, suggesting that this neuronal population has translational importance as a potential therapeutic target for obesity treatment.This study discovers that the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 indirectly inhibits the majority of orexigenic hindbrain NPY neurons via GABAreceptors by augmenting presynaptic GABA release. Chemogenetic activation of these NPY neurons effectively counteracts exendin-4 (Exn-4)-induced anorexigenic effect, whereas chemogenetic inhibition of them mimics the eating-suppressing effect of exendin-4. This study uncovers a mechanism by which Exn-4 inhibits orexigenic hindbrain NPY neurons, thereby providing new insights into how GLP-1 drugs suppress food intake. NPY NPY NPY NPY NPY NPY b b NEW & NOTEWORTHY
