Obese individuals show increased activation of brain reward regions, and fasting increases the desire to eat in obese more than lean humans. Agouti-related peptide (AgRP) neurons in the arcuate nucleus are one key neuronal population that link homeostatic detection of hunger with dopamine pathways in the brain that control motivation and reward. To assess the role of metabolic sensing in AgRP neurons and the effects on reward and motivation, we studied mice lacking carnitine acetyltransferase (Crat) in AgRP neurons, as our previous studies show that Crat in AgRP neurons plays a crucial role during the metabolic shift from fasting to refeeding. Thus, we hypothesized that Crat in AgRP neurons couples the detection of metabolic state with food reward value and motivated behaviors.
Two-bottle choice tests show that Crat in AgRP neurons is important for sensing of the caloric value of sweet solutions since fasting increases sucrose consumption in WT more than in KO mice. Moreover, during fasting WT mice will still consume sucrose spiked with quinine (unpleasant tastant) to consume calories as required, whereas KO mice do not.
The dorsal striatum mediates the effects of calorie, and not taste, reward processing. Therefore, we developed a whole animal PET/CT f18DOPA scan method to estimate dopamine activity of the dorsal and ventral striatum system. Our results showed lower f18DOPA uptake in the dorsal striatum of KO mice in response to reward stimulus compared to WT mice and no differences in ventral striatum f18DOPA uptake.
These studies highlight that Crat in AgRP neurons is crucial for the caloric assessment of sugar solutions and may link the detection of energy deficit with increased dopamine signaling in the dorsal striatum to ultimately impact food reward and motivation.