High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism

Abstract

The mammalian CNS is considered to be autonomous in lipid metabolism. Glial cells, in particular astrocytes, have been shown to be highly active in lipid synthesis and secretion. To determine the importance of astrocytes as lipid providers in the brain, we generated mice in which the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) was deleted from astrocytes using cre/lox technology. SCAP mutant mice showed microcephaly, without effects on astrocyte survival. SCAP deletion in astrocytes led to a loss of cholesterol and fatty acid synthesis pathways. SCAP mutants showed progressive motor deficits, dyskinesia, and reduced anxiety. Interestingly, SCAP mutants showed changes in brain sterol and fatty acid profiles that were concordant with reduced lipid synthesis as well as with increased uptake of dietary lipids. Accordingly, a high-fat diet rich in cholesterol and monounsaturated fatty acids, but not a fish oil diet rich in polyunsaturated fatty acids, improved motor deficits and survival of the mutant mice. These observations establish a critical role for astrocytes in brain lipid metabolism and demonstrate that dietary lipids can rescue astrocyte-mediated lipid deficiency. The ability to correct these neurological deficits suggests that lipid supplementation may serve as a treatment for brain disorders associated with defective astrocyte lipid synthesis.