Vagal Sensory Neuron-Derived FGF3 Regulates Insulin Secretion and Energy Balance

The vagus nerve has long been associated with the regulation of energy balance. However, the identity of the molecules mediating these effects remain largely unknown. Here, we used RNA sequencing to interrogate the molecular repertoire of the mouse vagal afferents. We found that Fgf3 mRNA is upregulated in the jugular-nodose ganglia under acute insulin resistance. Together, we provide evidence for efferent-like roles of the vagal afferents and identify Fgf3 as a novel vagal sensory-derived metabolic hormone that regulates insulin secretion and energy expenditure. Systemic and vagal sensory overexpression of Fgf3 increased insulin secretion, improved glucose excursion, and enhanced energy expenditure and physical activity. Selective overexpression of Fgf3 in pancreas-projecting vagal afferents recapitulated similar favorable metabolic outcomes. Conversely, mice lacking Fgf3 specifically in the vagal afferents innervating the pancreas exhibited impaired glucose clearance and blunted glucose-stimulated insulin release in high-fat diet settings.