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

Vagal sensory neurons (VSN) communicate information regarding the peripheral glycemic state to the brain. However, the vagal circuits that sense and respond to continuous fluctuations in peripheral glucose levels to modify hormone release and fine-tune feeding behavior are unclear. Here, we show that VSN regulate glucose homeostasis via sensing glucose and communicating with insulin producing β-cells. Neuronal tracing combined with in-situ hybridization and immunofluorescence revealed that VSN expressing cocaine and amphetamine regulated transcript (VSN-CART) are anatomically connected with β-cells. Chemogenetic stimulation of VSN-CART increased levels of acetylcholine and insulin along with reductions in glucose levels. In contrast, silencing of VSN-CART suppressed glucose-stimulated insulin secretion and led to glucose intolerance. VSN-CART responded differentially to feeding status via changes to the vagal transcriptome and brainstem neuronal activity. Activation of VSN-CART suppressed whereas silencing increased food consumption. Neuronal activity measurements and two-photon Ca2+ imaging revealed that VSN-CART serve a dose-dependent glucose excitatory function. We propose that the VSN-CART – β-cell neural circuit dynamically senses glucose levels to modulate insulin secretion, feeding behavior and glucose homeostasis.