An advanced finding of the present work is the specification of DA neurons as a target of metabolic actions of FoxO1 in the CNS. As mentioned above, the DAT-cre activity is homogeneous and limited in DA neurons1517. Therefore, the observed phenotypes in FoxO1DAT KO mice could be attributed specifically to the DA neurons. In this regard, our data provide strong evidence that FoxO1 in DA neurons not only plays a role in the control of feeding behaviour but is also critical for the regulation of energy expenditure and metabolic homoeostasis. The DA neuron system is considered part of the reward system regulating feeding behaviour especially those related to reward value of food, and is associated with over-eating and obesity development1949. However, recent findings suggest that midbrain DA neurons are not homogenous. They receive neuronal inputs from diverse sources and project to different output sites as well5051. It would be interesting to investigate whether FoxO1 acts on a specific subset of DA neurons to regulate energy expenditure while other subsets of DA neurons contribute to the food reward modulation. This, together with the precise brain site of DA neurons where FoxO1 mediates the aforementioned metabolic phenotypes, warrants further studies.
