biostudies-literatureTahiri ANational Institute of Neurological Disorders and StrokeJapan IDDM NetworkNational Institute of Diabetes and Digestive and Kidney DiseasesNIMH NIH HHSNational Center for Complementary and Integrative HealthMinistry of Education, Culture, Sports, Science and TechnologyNational Institute of Diabetes and Digestive and Kidney Diseases Division of Diabetes Endocrinology and Metabolic DiseasesNCCIH NIH HHSNIDDK NIH HHSNINDS NIH HHSNational Institute of Mental HealthNew York Medical CollegeHuman Islet Research NetworkJapan Science and Technology AgencyNew Jersey Council on Developmental DisabilitiesRobert Wood Johnson Foundation51-61.e4https://www.ebi.ac.uk/biostudies/studies/S-EPMC11706709biostudies-literatureUnknown60(1)Vagal nerve stimulation has emerged as a promising modality for treating a wide range of chronic conditions, including metabolic disorders. However, the cellular and molecular pathways driving these clinical benefits remain largely obscure. Here, we demonstrate that fibroblast growth factor 3 (Fgf3) mRNA is upregulated in the mouse vagal ganglia under acute metabolic stress. Systemic and vagal sensory overexpression of Fgf3 enhanced glucose-stimulated insulin secretion (GSIS), improved glucose excursion, and increased energy expenditure and physical activity. Fgf3-elicited insulinotropic and glucose-lowering responses were recapitulated when overexpression of Fgf3 was restricted to the pancreas-projecting vagal sensory neurons. Genetic ablation of Fgf3 in pancreatic vagal afferents exacerbated high-fat diet-induced glucose intolerance and blunted GSIS. Finally, electrostimulation of the vagal afferents enhanced GSIS and glucose clearance independently of efferent outputs. Collectively, we demonstrate a direct role for the vagal afferent signaling in GSIS and identify Fgf3 as a vagal sensory-derived metabolic factor that controls pancreatic β-cell activity.Developmental cellVagal sensory neuron-derived FGF3 controls insulin secretion.PMC11706709R01DK122167R15 NS130456R01 DK12216774260UC4 DK104162U24 DK104162CAUT24DFP23H03324R21 AT011387R15NS130456RF1 MH120144R01 DK131452U01 DK104162Moon SZhao JYInoue RYoussef AWang LKwon HEl Ouaamari AUlloa LTahiri ABerroug LNguyen XTAShirakawa JAlsarkhi LPang ZPfalseVagal sensory neuron-derived FGF3 controls insulin secretion.Vagal nerve stimulation has emerged as a promising modality for treating a wide range of chronic conditions, including metabolic disorders. However, the cellular and molecular pathways driving these clinical benefits remain largely obscure. Here, we demonstrate that fibroblast growth factor 3 (Fgf3) mRNA is upregulated in the mouse vagal ganglia under acute metabolic stress. Systemic and vagal sensory overexpression of Fgf3 enhanced glucose-stimulated insulin secretion (GSIS), improved glucose excursion, and increased energy expenditure and physical activity. Fgf3-elicited insulinotropic and glucose-lowering responses were recapitulated when overexpression of Fgf3 was restricted to the pancreas-projecting vagal sensory neurons. Genetic ablation of Fgf3 in pancreatic vagal afferents exacerbated high-fat diet-induced glucose intolerance and blunted GSIS. Finally, electrostimulation of the vagal afferents enhanced GSIS and glucose clearance independently of efferent outputs. Collectively, we demonstrate a direct role for the vagal afferent signaling in GSIS and identify Fgf3 as a vagal sensory-derived metabolic factor that controls pancreatic β-cell activity.2025-01-01T00:00:00Z2025 Jan2026-06-06T20:04:11.161Z2026-06-04T03:14:56.009ZS-EPMC117067093941378210.1016/j.devcel.2024.09.016