Fats and Sugars Recruit Distinct Gut‐Brain Circuits To Control Food Intake And Reward.

R29 --> 576.1 --> The high‐fat high‐sugar food environment has been implicated as a driver of the obesity epidemic. Nodose ganglia (NG) neurons transmit post‐ingestive signals, including fat and sugar intake, from the gut to the brain. Previous data revealed distinct vagal circuits are required for post‐ingestive fat and sugar reinforcement, but whether these signals converge onto overlapping reward circuits is unclear. Methods: To address this, we used FosTRAP mice to genetically label whole‐brain neuronal responses to discreet time‐restricted stimuli. Using genetic‐encoded reporter (tdTom) expression and cFos immunolabeling we compared neural responses to intragastric stimuli at two separate timepoints in the same animal. Results: Repeated intragastric infusion of the same macronutrient resulted in high colocalization between tdTom and cFos labeling (>70%) in neurons of a previously identified gut‐reward circuit (NTS, PBN, SNc, dorsal striatum). Equicaloric infusion of fat or sugar at two separate timepoints significantly reduced colocalization of tdTom and cFos labeling (<30%), suggesting that fat and sugar recruit parallel but largely distinct reward circuits. Viral‐mediated caspase ablation of sugar‐sensing NG neurons abolished activation of the reward circuitry for sugar, but not fat; confirming this is a vagally‐mediated mechanism. Optogenetic stimulation of fat‐sensing NG neurons is sufficient to condition operant behavior. Microdialysis in response to equicaloric intragastric infusions of fat or sugar resulted in similar dopamine efflux in the dorsal striatum. To obtain the same level of dopamine efflux, more calories of an equicaloric fat‐sugar combination are required, correlating with compensatory increased intake of fat‐sugar solution. Conclusion: There are labeled lines for vagally‐mediated fat or sugar reward. Reduced reward in response to fat‐sugar combinations may explain the inclination to overindulge in high‐fat high‐sugar foods, and have broad implications for the pathogenesis of obesity. [ABSTRACT FROM AUTHOR]