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BackgroundKetone bodies are known to substitute for glucose as brain fuel when glucose availability is low. Ketogenic diets have been described as neuroprotective. Similar data have been reported for triheptanoin, a fatty oil and anaplerotic compound. In this study, we monitored the changes of energy metabolites in liver, blood, and brain after transient brain ischemia to test for ketone body formation induced by experimental stroke.Methods and ResultsMice were fed a standard carbohydrate‐rich diet or 2 fat‐rich diets, 1 enriched in triheptanoin and 1 in soybean oil. Stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by reperfusion. Mice were sacrificed, and blood plasma and liver and brain homogenates were obtained. In 1 experiment, microdialysis was performed. Metabolites (eg glucose, β‐hydroxybutyrate, citrate, succinate) were determined by gas chromatography–mass spectrometry. After 90 minutes of brain ischemia, β‐hydroxybutyrate levels were dramatically increased in liver, blood, and brain microdialysate and brain homogenate, but only in mice fed fat‐rich diets. Glucose levels were changed in the opposite manner in blood and brain. Reperfusion decreased β‐hydroxybutyrate and increased glucose within 60 minutes. Stroke‐induced ketogenesis was blocked by propranolol, a β‐receptor antagonist. Citrate and succinate were moderately increased by fat‐rich diets and unchanged after stroke.ConclusionsWe conclude that brain ischemia induces the formation of β‐hydroxybutyrate (ketogenesis) in the liver and the consumption of β‐hydroxybutyrate in the brain. This effect seems to be mediated by β‐adrenergic receptors.

SummarySleep is induced by sleep-active neurons that depolarize at sleep onset to inhibit wake circuits. Sleep-active neurons are under the control of homeostatic and allostatic mechanisms that determine sleep need. However, little is known about the molecular and circuit mechanisms that translate sleep need into the depolarization of sleep-active neurons. During many conditions in C. elegans sleep induction requires a sleep-active neuron called RIS. Here, we defined the transcriptome of RIS to discover that genes of the Epidermal Growth Factor Receptor (EGFR) signaling pathway are expressed in RIS. With cellular stress, EGFR activates RIS, and RIS induces sleep. Activation of EGFR signaling in the ALA neuron has previously been suggested to promote sleep independently of RIS. Unexpectedly, we found that ALA activation promotes RIS depolarization. Our results suggest that ALA is a sedating neuron with two separable functions. (1) It inhibits specific wakefulness behaviors independently of RIS, (2) and it activates RIS to induce sleep. Whereas ALA plays a strong role in surviving cellular stress, surprisingly, RIS does not. In summary, EGFR signaling can induce sleep-active neuron depolarization by an indirect mechanism through activation of the sedating ALA neuron that acts upstream of the sleep-active RIS neuron as well as through a direct mechanism using EGFR signaling in RIS. Sedation rather than sleep appears to be important for increasing survival following cellular stress, suggesting that sedation and sleep play different roles in restoring health.Highlights-The transcriptome of the sleep-active RIS neuron reveals the presence of the EGFR signaling machinery-EGFR activates RIS directly upon cellular stress to induce sleep bouts-In parallel, EGFR activates RIS indirectly through the sedating ALA neuron-Sedation rather than sleep bouts support survival following cellular stress