Brain-derived ketone bodies can replace glucose to power neural function.

The brain is sensitive to disruptions in glucose metabolism, requiring constant delivery to support neural activity. Here, we discovered a vertebrate with the surprising capacity to abandon glucose metabolism and replace it with ketone bodies produced entirely within the brain. In frogs-animals with seemingly typical glucose demands-hibernation shifts brain bioenergetics to allow ketone bodies made within the brain to sustain neural activity without ATP from glucose metabolism. This involves, in part, the upregulation of fatty acid catabolism, ketone body synthesis, and transport from astrocytes to neurons to maintain synaptic transmission. Brain-derived ketone bodies also prevent decrements in activity that otherwise occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise impair neural performance. Overall, these results reveal a capacity for the vertebrate brain to temporarily abandon glucose while maintaining costly functions using locally sourced ketone bodies independent from body energy stores.