Vagal sensory neuron-derived FGF3 controls insulin secretion

  • Dev Cell. 2025 Jan 6;60(1):51-61.e4. doi: 10.1016/j.devcel.2024.09.016.
Azeddine Tahiri  1 ,  Ayman Youssef  2 ,  Ryota Inoue  3 ,  Sohyun Moon  4 ,  Lamyaa Alsarkhi  1 ,  Laila Berroug  1 ,  Xuan Thi Anh Nguyen  5 ,  Le Wang  5 ,  Hyokjoon Kwon  5 ,  Zhiping P Pang  5 ,  Jerry Yingtao Zhao  4 ,  Jun Shirakawa  3 ,  Luis Ulloa  2 ,  Abdelfattah El Ouaamari  6
Affiliations
  • 1. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
  • 2. Center for Perioperative Organ Protection, Department of Anesthesiology, Duke University, Durham, NC 27710, USA.
  • 3. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan.
  • 4. Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
  • 5. Child Health Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
  • 6. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA; Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA. Electronic address: [email protected].
PMID: 39413782 DOI: 10.1016/j.devcel.2024.09.016
Abstract

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.

Keywords
FGF3; RNA sequencing; autonomic nervous system; glucose homeostasis; insulin resistance; insulin secretion; islet pancreatic β cells; sensory neurons; vagal nerve stimulation; vagus nerve.
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