In the Brain, It Is Not All about Sugar.

The maintenance of energetic homeostasis relies on a tight balance between glycolysis and mitochondrial oxidative phosphorylation. The case of the brain is a peculiar one, as although entailing a constant demand for energy, it is believed to rely mostly on glucose, particularly at the level of neurons. Nonetheless, this has been challenged by studies that show that alternatives such as lactate, ketone bodies, and glutamate can be used as fuels to sustain neuronal activity. The importance of fatty acid (FA) metabolism to this extent is still unclear, albeit sustaining a significant energetic output when compared to glucose. While several authors postulate a possible role of FA for the energetic homeostasis of the brain, several others point out the intrinsic features of this pathway that make its contribution difficult to explain in the context of neuronal bioenergetics. Moreover, fueling preference at the synapse level is yet to be uncovered. In this review, we discuss in detail the arguments for and against the brain usage of FA. Furthermore, we postulate that the importance of this fuel may be greater at the synapse, where local mitochondria possess a set of features that enable a more effective usage of this fuel source.