Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior

Objective: The vagus nerve provides a direct line of communication between the gut and the brain for proper regulation of energy balance and glucose homeostasis. Short-chain fatty acids (SCFAs) produced via gut microbiota fermentation of dietary fiber have been proposed to regulate host metabolism and feeding behavior via the vagus nerve, but the molecular mechanisms have not yet been elucidated. We sought to identify the G-protein-coupled receptors within vagal neurons that mediate the physiological and therapeutic benefits of SCFAs. Methods: SCFA, particularly propionate, signaling occurs via free fatty acid receptor 3 (FFAR3), that we found expressed in vagal sensory neurons innervating throughout the gut. The lack of cell-specific animal models has impeded our understanding of gut/brain communication; therefore, we generated a mouse model for cre-recombinase-driven deletion of Ffar3. We comprehensively characterized the feeding behavior of control and vagal-FFAR3 knockout (KO) mice in response to various conditions including fasting/refeeding, western diet (WD) feeding, and propionate supplementation. We also utilized ex vivo organotypic vagal cultures to investigate the signaling pathways downstream of propionate FFAR3 activation. Results: Vagal-FFAR3KO led to increased meal size in males and females, and increased food intake during fasting/refeeding and WD challenges. In addition, the anorectic effect of propionate supplementation was lost in vagal-FFAR3KO mice. Sequencing approaches combining ex vivo and in vivo experiments revealed that the cross-talk of FFAR3 signaling with cholecystokinin (CCK) and leptin receptor pathways leads to alterations in food intake. Conclusion: Altogether, our data demonstrate that FFAR3 expressed in vagal neurons regulates feeding behavior and mediates propionate-induced decrease in food intake.