The Complementary Roles of Glucose and Lactate in Meeting Neuronal Energetic Needs: An Investigation into the Modulation of Cortical Metabolism and Extracellular Metabolite Pools in the Mouse

Abstract

Our knowledge of cerebral metabolism is shifting towards an understanding and appreciation of non-neuronal and non-glucose contributions to meeting the brains high energetic needs. Specifically, astrocytes are hypothesized to provide metabolites that sustain neuronal energy needs as well as modulate neuronal signalling. This metabolic collaboration between cellular compartments occurs in the extracellular space of the brain where astrocytes can provide endogenously created metabolites or regulate cerebral blood flow and subsequently metabolite delivery. The work presented herein investigated the contribution of the blood brain barrier and non-glucose fuels (e.g. lactate) in the maintenance of the extracellular glucose and lactate pools. The transport of blood-borne alternative fuels across the blood-brain barrier, namely lactate, are essential to maintaining extracellular metabolite pools and thus play an important role in the metabolic cooperation between the various compartments of the brain (i.e. neurons and astrocytes) and body (i.e. central and peripheral systems). Through observations of preferential upregulation of monocarboxylate pathways, we hypothesize a larger scale collaboration in which the body metabolize various fuels towards common downstream products (i.e. glucose and lactate), enabling the brain to optimize but a few pathways while reaping benefits from a wide variety of sources. Commonly observed metabolic dysregulation in brain pathologies may underscore an inability to flexibly adapt these pathways to changing environmental bioenergetic challenges. The role of peripheral metabolites (i.e. lactate) in maintaining extracellular metabolite pools is an important consideration in the on-going debate about the neuronal use of astrocyte derived lactate and relevant context for future modeling studies.