A carnitine transporter at the blood-brain barrier modulates sleep via glial lipid metabolism in <i>Drosophila</i>.

Abstract

To regulate brain function, peripheral compounds must traverse the blood-brain barrier (BBB), an interface between the brain and the circulatory system. To determine whether specific transport mechanisms are relevant for sleep, we conducted a BBB-specific inducible RNAi knockdown (iKD) screen for genes affecting sleep in <i>Drosophila</i>. We observed reduced sleep with knockdown of solute carrier <i>CG6126</i>, a carnitine transporter, as determined by isotope flux. Our findings suggest that <i>CG6126</i> regulation of sleep is through the role of the carnitine shuttle in regulating fatty acid metabolism as lipid droplets accumulate in the brains of <i>CG6126</i> BBB iKD flies. Knocking down mitochondrial carnitine transferases in non-BBB glial cells mimicked the reduced sleep of the <i>CG6126</i> BBB iKD flies, while bypassing the necessity of carnitine transport with dietary medium-chain fatty acids or palmitoylcarnitine rescued sleep. We propose that carnitine transport via <i>CG6126</i> promotes brain fatty acid metabolism necessary for maintaining sleep.