METABOLIC FLEXIBILITY OF CNS CELLS UNDER GLUCOSE DEPRIVATION

The brain, despite accounting for only 2% of body weight, consumes a disproportionate amount of energy and relies largely on glucose to sustain its high metabolic demand. Preserving energy homeostasis is essential for proper central nervous system (CNS) function, and reduced metabolic flexibility has been linked to neurodegenerative processes. Long-chain fatty acids represent a potential alternative substrate for mitochondrial metabolism, as their oxidation yields high amounts of ATP and requires mitochondrial import via carnitine palmitoyltransferase 1A (CPT1A). Here, we examined how fatty acid availability influences metabolic and functional responses of CNS cells under conditions of hypoglycemia. Using primary neurons, astrocytes, and oligodendrocytes exposed to hypoglycemia, we assessed mitochondrial function and cellular energy status in the presence of long-chain fatty acids. CPT1A expression was detected across CNS cell types, supporting their capacity to engage fatty acid–dependent metabolic pathways. Hypoglycemia induced cell-type–specific metabolic responses, with glial cells showing a relative preservation of mitochondrial activity compared to neurons, while fatty acid supplementation modulated mitochondrial parameters and mitochondrial membrane potential, suggesting altered mitochondrial coupling during metabolic stress. Because axonal conduction is highly energy dependent, we further investigated whether fatty acid metabolism can sustain axonal function under glucose deprivation. Electrophysiological recordings from acutely isolated optic nerves revealed that fatty acids significantly improved the recovery of evoked compound action potentials following glucose deprivation. Together, these findings demonstrate heterogeneous metabolic adaptations among CNS cell types and identify fatty acid metabolism as a key contributor to cellular energy homeostasis and axonal function under hypoglycemic conditions.