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  3. GLP-1 receptor agonist exendin-4 suppresses food intake by inhibiting hindbrain orexigenic NPY neurons

GLP-1 receptor agonist exendin-4 suppresses food intake by inhibiting hindbrain orexigenic NPY neurons

  • Am J Physiol Endocrinol Metab. 2025 May 1;328(5):E661-E674. doi: 10.1152/ajpendo.00528.2024.
Jiayi Shen 1 2 3,  Mengtian Wang 1 2 4,  Guodong Pang 1 2 3,  Yan Zhang 1 2 3,  Jian Zhang 1 2 4,  Yuyan Shi 1 2 3,  Ji Liu 1 2 4,  Cheng Zhan 1 2 3
Affiliations

Affiliations

  • 1 Department of Hematology, The First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, People's Republic of China.
  • 2 Department of Endocrinology, The First Affiliated Hospital of USTC, Hefei National Research Center for Physical Sciences at the Microscale, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, People's Republic of China.
  • 3 National Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, CAS Key Laboratory of Brain Function and Disease, University of Science and Technology of China, Hefei, People's Republic of China.
  • 4 School of Biomedical Engineering, School of Information Science and Technology, University of Science and Technology of China, Hefei, People's Republic of China.
PMID: 40126941 DOI: 10.1152/ajpendo.00528.2024
Abstract

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 NTSNPY neurons. We discovered that the GLP-1R agonist exendin-4 inhibits NTSNPY neuronal activity via GABAb receptors by augmenting presynaptic GABA release. We also explored the contribution of NTSNPY neurons to exendin-4-mediated eating suppression. Interestingly, chemogenetic activation of NTSNPY neurons effectively counteracted exendin-4-induced anorexigenic effect. Moreover, chemogenetic inhibition of NTSNPY neurons mimicked the eating-suppressing effect of exendin-4. Collectively, our findings highlight a population of orexigenic NTSNPY neurons 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.NEW & NOTEWORTHY 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 GABAb receptors 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.

Keywords

GABAb receptors; GLP-1 receptor; food intake; neuropeptide Y neurons; the nucleus tractus solitarius.

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