Modulation of sleep by trafficking of lipids through the Drosophila blood brain barrier

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Abstract

Endocytosis through Drosophila glia is a significant determinant of sleep amount and occurs preferentially during sleep in glia of the blood brain barrier (BBB). To identify metabolites whose trafficking is mediated by sleep-dependent endocytosis, we conducted metabolomic analysis of flies that have increased sleep due to a block in glial endocytosis. We report that acylcarnitines, fatty acids conjugated to carnitine to promote their transport, accumulate in heads of these animals. In parallel, to identify transporters and receptors whose loss contributes to the sleep phenotype caused by blocked endocytosis, we screened genes enriched in barrier glia for effects on sleep. We find that knockdown of lipid transporters LRP1&2 or of carnitine transporters ORCT1&2 increases sleep. In support of the idea that the block in endocytosis affects trafficking through specific transporters, knockdown of LRP or ORCT transporters also increases acylcarnitines in heads. We propose that lipid species, such as acylcarnitines, are trafficked through the BBB via sleep-dependent endocytosis, and their accumulation reflects an increased need for sleep.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1,2, 3, 4, 5, 6, 7, 8 and Figure1-supplement Figur1, Figure 2- figure supplement 1, Figure 3- figure supplement 1.3 ,4, 5 ,6, 7, 8. Figure 4- figure supplement 1, 2, 3, 4, 5, 6.

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Amita Sehgal

Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States

Competing interests
Amita Sehgal, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-7354-9641
Fu Li

Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States

Competing interests
No competing interests declared.
Gregory Artiushin

Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States

For correspondence
grega@jhu.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-1615-3012

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120757)

Amita Sehgal

Howard Hughes Medical Institute

Amita Sehgal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.