Elsevier

Experimental Neurology

Volume 309, November 2018, Pages 23-31
Experimental Neurology

Review Article
Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

https://doi.org/10.1016/j.expneurol.2018.07.009Get rights and content

Highlights

  • Glucose, lactate and acetate are used as metabolic fuels in the nervous system

  • Function of energy metabolites dependent on expression of specific metabolic transporters

  • Brain glucose transporters are primarily expressed in blood vessels and glia

  • Monocarboxylate transporters support axon function in the brain and nerve regeneration in the peripheral nervous system

  • Disruption of glucose or monocarboxylate transporters leads to cellular dysfunction and neurologic disease

Abstract

The brain is, by weight, only 2% the volume of the body and yet it consumes about 20% of the total glucose, suggesting that the energy requirements of the brain are high and that glucose is the primary energy source for the nervous system. Due to this dependence on glucose, brain physiology critically depends on the tight regulation of glucose transport and its metabolism. Glucose transporters ensure efficient glucose uptake by neural cells and contribute to the physiology and pathology of the nervous system. Despite this, a growing body of evidence demonstrates that for the maintenance of several neuronal functions, lactate, rather than glucose, is the preferred energy metabolite in the nervous system. Monocarboxylate transporters play a crucial role in providing metabolic support to axons by functioning as the principal transporters for lactate in the nervous system. Monocarboxylate transporters are also critical for axonal myelination and regeneration. Most importantly, recent studies have demonstrated the central role of glial cells in brain energy metabolism. A close and regulated metabolic conversation between neurons and both astrocytes and oligodendroglia in the central nervous system, or Schwann cells in the peripheral nervous system, has recently been shown to be an important determinant of the metabolism and function of the nervous system. This article reviews the current understanding of the long existing controversies regarding energy substrate and utilization in the nervous system and discusses the role of metabolic transporters in health and diseases of the nervous system.

Introduction

Neurons and glia are the primary cellular components that perform the functions of the central and peripheral nervous system (CNS and PNS, respectively). Glia maintain tissue homeostasis, form myelin, regulate development, and contribute to diverse neuropathophysiologies in the CNS and the PNS. Besides providing structural and metabolic support to neurons, glia also contribute to recovery following neuronal injuries. Neurons transmit signals over long distances through their axons; and these axons require an enormous energy supply to maintain their function. Axons are closely associated with glial cells that support their function and prevent degeneration.

Research over the last decades has shown that the brain is an organ of unusually high metabolic demand that utilizes 20% of the total glucose and 20% of the total oxygen in the human body (Magistretti and Allaman, 2015). Studies have reported glucose as the obligatory energy substrate for brain, where it is almost fully oxidized (Kety and Schmidt, 1948; Sokoloff, 1960). Similarly, further studies at the whole organ level have provided some refinements to this view, suggesting that ketone bodies fulfill the energy requirements of the brain under particular conditions, including fasting, uncontrolled diabetes and breast-fed newborn babies (Magistretti, 1999). Additionally, several studies over the last few years have illustrated the significance of lactate as an energy substrate for the brain (Baltan, 2015; Castillo et al., 2015; Machler et al., 2016; Matsui et al., 2017; Magistretti and Allaman, 2018). Specifically, findings from in vitro and in vivo studies demonstrate that lactate sustains neuronal activity during glucose deprivation (Wyss et al., 2011; Sobieski et al., 2018). The astrocyte-neuron lactate shuttle hypothesis (ANLSH) suggests that astrocyte-derived L-lactate is taken up by neurons via monocarboxylate transporters (MCTs), metabolic transporters for monocarboxylates, and used as an energy substrate, possibly in preference to glucose. Though it was proposed over twenty years ago (Magistretti et al., 1993; Pellerin and Magistretti, 1994), ANLSH remains controversial and not fully accepted. A recent study claims that during fasting conditions, glucose contributes indirectly (via circulating lactate) to tissue TCA metabolism in all tissues except the brain (Hui et al., 2017). Additionally, a study modeling the kinetic characteristics and cellular concentrations of the neuronal glucose and lactate transporters opposes the ANLSH primarily due to the fact that neuronal glucose transporter, GLUT3, has higher affinity for glucose than the astrocytic counterpart, GLUT1, an, indicating that glucose may be primarily transported to and consumed by neurons (Simpson et al., 2007). Finally, studies suggest that neurons have the capacity to boost their own glycolysis and potentially export rather than import lactate during brain activation or in response to stimulation (Diaz-Garcia et al., 2017; Yellen, 2018). This article addresses these controversies and reviews different aspects of glia-axon energy metabolism in health and diseases of the nervous system focusing on neural energy substrates consumption and metabolism, and their transporters.

Section snippets

Fuels to neural cells: glucose, its “by-product” lactate, and occasionally acetate too!

About 20% of our circulating glucose enters the brain, suggesting that glucose is the primary energy source for the brain. For some time, it had been accepted without reservation that all brain metabolic pathways are subsequent to glucose until the proposition of the ANLSH (Magistretti, 2008, Pellerin and Magistretti, 2012). The ANLSH challenged this precept, stating that activity-dependent uptake of glucose takes place in astrocytes that subsequently metabolize the glucose anaerobically to

Glucose transporters ensure efficient glucose uptake by neural cells

Glucose is transported across the cell membrane by facilitative diffusion mediated by members of the GLUT family, which belongs to the major facilitator superfamily of membrane transporters (Pao et al., 1998; Thorens and Mueckler, 2010). Most of the GLUTs catalyze the ATP-dependent bidirectional transfer of glucose across membranes. GLUT 1-4 are the well-studied/established glucose transporters and have distinct regulatory and/or kinetic properties, suggesting their cell-specific role. GLUT1

Monocarboxylate transporters are widely expressed metabolic transporters in central and peripheral nervous systems

The existence of glia-axon metabolic interactions in the CNS and PNS is most likely mediated by the monocarboxylate transporters (MCTs) (Fig. 2 and Fig. 3). MCTs are extracellular membrane channels that can transport monocarboxylates (such as lactate, pyruvate and ketone bodies), along with protons, down their concentration gradient across membranes (Garcia et al., 1994). MCTs are vital for metabolic shuttling between glia and neurons and facilitate the functioning of lactate as a preferred

Conclusions

It is now more than half a century since glia were acknowledged to contribute to neuronal energy metabolism. Glia are now widely recognized as dynamic cells that sense neuronal metabolic changes and regulate metabolism by transferring metabolites from glia to neurons. Both central and peripheral neurons alternate between glucose and lactate as an effective energy source, but prefer lactate during increased energy demand. Astrocytes and oligodendrocytes in the CNS, and potentially Schwann cells

Acknowledgements

This work was supported by the National Institutes of Health (R01NS086818).

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