Genetic Identification of Vagal Sensory Neurons That Control Feeding

Energy homeostasis requires precise measurement of the quantity and quality of ingested food. The vagus nerve innervates the gut and can detect diverse interoceptive cues, but the identity of the key sensory neurons and corresponding signals that regulate food intake remains unknown. Here, we use an approach for target-specific, single-cell RNA sequencing to generate a map of the vagal cell types that innervate the gastrointestinal tract. We show that unique molecular markers identify vagal neurons with distinct innervation patterns, sensory endings, and function. Surprisingly, we find that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect. Peripheral manipulations combined with central recordings reveal that intestinal mechanoreceptors, but not other cell types, potently and durably inhibit hunger-promoting AgRP neurons in the hypothalamus. These findings identify a key role for intestinal mechanoreceptors in the regulation of feeding. [Display omitted] •A molecular map of vagal sensory neurons innervating the abdominal viscera•Molecular identity correlates with innervation pattern and axon terminal morphology•Stimulation of vagal IGLE mechanoreceptors, but not mucosal endings, inhibits feeding•Intestine distension or mechanoreceptor activation inhibits hypothalamic AgRP neurons A single-cell approach cataloging the sensory neurons in the vagus nerve identifies populations that suppress hunger through mechanosensation in the intestine.