A distinct vagus-beta cell neural circuit senses glucose and modulates insulin secretion.

Vagal sensory neurons (VSN) convey peripheral glycemic information to the brain, yet the specific pathways that continuously sense glucose fluctuations and regulate hormone secretion and feeding remain poorly defined. Here, we examined the anatomical and functional aspects of an integrated circuit originating in pancreatic β-cells, projecting through the nodose ganglion, and engaging the dorsal vagal complex to relay feedback to β-cells. We performed monosynaptic viral fluorescent tracing, RNA sequencing, RNAscope, chemogenetics, optogenetics, neuronal silencing, automated glucose telemetry, feeding assays, neural activity measurements, glucose sensing, and intracellular calcium measurements using 2-photon microscopy. The vagal transcriptome exhibited metabolic state- and diet-dependent regulation of pathways involved in glucose sensing, insulin secretion, and glucose homeostasis. Viral tracing identified abundant VSN innervating β-cells, including a subset expressing cocaine- and amphetamine-regulated transcript (VSNCART), whose activity was modulated by metabolic state and altered brainstem neuronal activity. VSNCART stimulation increased acetylcholine and C-peptide secretion and lowered blood glucose in a metabolic state-dependent manner, whereas silencing impaired glucose-stimulated insulin secretion and induced glucose intolerance. VSNCART activation suppressed food intake, while inhibition increased feeding, also in a metabolic state-dependent manner. C-Fos labeling and two-photon Ca2+ imaging revealed that VSNCART neurons exhibit dose-dependent excitatory responses to glucose. We identified a vagal sensory neuron-β-cell circuit and showed that VSNCART neurons sense glucose to regulate insulin secretion, feeding behavior, and glucose homeostasis.