Separate gut-brain circuits for fat and sugar reinforcement combine to promote overeating.

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits is poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for the detection of dietary fats and sugars. Using activity-dependent genetic capture of vagal neurons activated in response to gut infusions of nutrients, we demonstrate the existence of separate gut-brain circuits for fat and sugar sensing that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases nigrostriatal dopamine release and overeating compared with fat or sugar alone. This work provides new insights into the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts. [Display omitted] • Intestinal fats and sugars are sensed by distinct vagal populations • Nutrient-sensing vagal sensory neurons are necessary and sufficient for reinforcement • Both fat and sugar cause dopamine release by engaging separate central reward circuits • Combining fat and sugar supra-additively increases dopamine efflux and eating McDougle et al. unveil gut-brain circuits for sugar and fat consumption. Separate chemosensory vagal neurons respond to either post-ingestive fat or sugar and engage distinct but parallel downstream reward circuits, crucial for reinforcement. Foods combining fats and sugars simultaneously recruit both circuits promoting the subconscious drive to overeat obesogenic diets. [ABSTRACT FROM AUTHOR]