Obese individuals show increased activation of brain reward regions (mesolimbic and mesocortical dopamine projections from the ventral tegmental area [VTA]), and fasting increases the desire to eat in obese more than lean humans. It remains unclear how the brain receives, senses and integrates metabolic information that reinforce food value and motivate feeding behaviours. For example, does inappropriate sensing of metabolic need drive greater activation of brain pathways underlying motivation and reward? Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus 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. Previous studies show that Crat in AgRP neurons plays a crucial role during the metabolic shift from fasting to refeeding and thus we hypothesised that it might couple the detection of metabolic state with food reward value and motivated behaviours.
We show that Crat in AgRP neurons is important for sensing of the caloric value of sweet solutions since fasting increases sucrose consumption during states of fasting in WT more than in KO mice. Moreover, during fasting WT mice will still consume sucrose spiked with quinine (unpleasant tastant) in order to consume calories as required, whereas KO mice do not. Intriguingly KO mice continually consume more saccharin despite changes in metabolic state due to fasting. Current studies using operant conditioning to examine motivation to work for caloric versus non-caloric sweet solutions are underway. 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 food reward and motivation.