Intestinal gluconeogenesis (IGN) promotes metabolic benefits through activation of a gut-brain neural axis. However, the local mediator activating gluconeogenic genes in the enterocytes remains unknown. We show that (1) VIP signaling through VPAC1 receptor activates the intestinal glucose-6-phosphatase gene in vivo, (2) the activation of IGN by propionate is counteracted by VPAC1 antagonism, and (3) VIP-positive intrinsic neurons in the submucosal plexus are increased under the action of propionate. These data support the role of VIP as a local neuromodulator released by intrinsic enteric neurons and responsible for the induction through a VPAC1 receptor-dependent mechanism in enterocytes.