Myelin lipids as nervous system energy reserves

Abstract Neuronal functions and impulse propagation depend on the continuous supply of glucose 1,2 . Surprisingly, the mammalian brain has no obvious energy stores, except for astroglial glycogen granules 3 . Oligodendrocytes make myelin for rapid axonal impulse conduction 4 and also support axons metabolically with lactate 5–7 . Here, we show that myelin itself, a lipid-rich membrane compartment, becomes a local energy reserve when glucose is lacking. In the mouse optic nerve, a model white matter tract, oligodendrocytes survive glucose deprivation far better than astrocytes, by utilizing myelin lipids which requires oxygen and fatty acid beta-oxidation. Importantly, fatty acid oxidation also contributes to axonal ATP and basic conductivity. This metabolic support by fatty acids is an oligodendrocyte function, involving mitochondria and myelin-associated peroxisomes, as shown with mice lacking Mfp2. To study reduced glucose availability in vivo without physically starving mice, we deleted the Slc2a1 gene from mature oligodendrocytes. This caused a significant decline of the glucose transporter GLUT1 from the myelin compartment leading to myelin sheath thinning. We suggest a model in which myelin turnover under low glucose conditions can transiently buffer axonal energy metabolism. This model may explain the gradual loss of myelin in a range of neurodegenerative diseases 8 with underlying hypometabolism 9 .