Neuron-astrocyte metabolic coupling during neuronal stimulation protects against fatty acid toxicity

Abstract

GRAPHICAL ABSTACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC=\"FIGDIR/small/465237_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (57K):\norg.highwire.dtl.DTLVardef@1d6cbf4org.highwire.dtl.DTLVardef@e83c9corg.highwire.dtl.DTLVardef@e35b92org.highwire.dtl.DTLVardef@910303_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIHyperactive neurons generate and release excess peroxidated fatty acids (FAs)\nC_LIO_LIAstrocytes endocytose toxic FAs as lipoprotein particles, delivering them to lipid droplets\nC_LIO_LILipid droplets trigger upregulation of genes involved in metabolism and detoxification\nC_LIO_LIAstrocytes detoxify and consume FAs by mitochondrial oxidation in response to neural activity\nC_LI\n\nSUMMARYMetabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic, peroxidated fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by lipoprotein particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial {beta}-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Together, our findings reveal that FA metabolism between neurons and astrocytes is coupled in an activity-dependent manner to protect neurons from FA toxicity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.