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Front. Cell. Neurosci., 06 March 2019 | https://doi.org/10.3389/fn-

cel.2019.00082 (https://doi.org/10.3389/fncel.2019.00082)

The Strategic Location ofGlycogen and Lactate: FromBody Energy Reserve to BrainPlasticity

Corrado Calì (http://www.frontiersin.org/people/u/228629) , Arnaud Tau"enberger (http://www.frontiersin.org/people/u/660257)and Pierre Magistretti (http://www.frontiersin.org/people/u/1327)

Biological and Environmental Sciences and Engineering Division, King Abdullah

University of Science and Technology, Thuwal, Saudi Arabia

Brain energy metabolism has been the object of intense research inrecent years. Pioneering work has identified the different cell typesinvolved in energy production and use. Recent evidence hasdemonstrated a key role of L-Lactate in brain energy metabolism,producing a paradigm-shift in our understanding of the neuronalenergy metabolism. At the center of this shift, is the identificationof a central role of astrocytes in neuroenergetics. Thanks to theirmorphological characteristics, they are poised to take up glucosefrom the circulation and deliver energy substrates to neurons.Astrocyte neuron lactate shuttle (ANLS) model, has shown that themain energy substrate that astrocytes deliver to neurons is L-Lactate, to sustain neuronal oxidative metabolism. L-Lactate canalso be produced from glycogen, the storage form of glucose, whichis exclusively localized in astrocytes. Inhibition of glycogenmetabolism and the ensuing inhibition of L-Lactate production

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TABLE OF CONTENTS

Abstract

Introduction

The Astrocyte Neuron

Lactate Shuttle (ANLS)

Glycogen

Peripheral Lactate

Utilization

Lactate as a Metabolic

Bu"er Between Glucose

and Oxidative Metabolism

in Peripheral Tissues

Any Issues?

Author Contributions

Funding

Conflict of Interest

Statement

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leads to cognitive dysfunction. Experimental evidence indicatesthat the role of lactate in cognitive function relates not only to itsrole as a metabolic substrate for neurons but also as a signalingmolecule for synaptic plasticity. Interestingly, a similar metabolicuncoupling appears to exist in peripheral tissues plasma, wherebyglucose provides L-Lactate as the substrate for cellular oxidativemetabolism. In this perspective article, we review the knowninformation on the distribution of glycogen and lactate withinbrain cells, and how this distribution relates to the energy regimeof glial vs. neuronal cells.

Introduction

L-Lactate was isolated in the 18th century and found to be released bymuscle cells upon exertion, its physiological role been reduced, for a longtime, to a simple waste product of anerobic metabolism. Interesting workin the ’80s started to unveil the metabolic properties of L-Lactate inskeletal muscles (Brooks, 1985). In contrast, our understanding of theenergy metabolism in the central nervous system (CNS) was delayedbecause of the technical challenges in studying the brain compared to theperipheral organs. However, in the ’90s, it was proposed that astrocytesrelease L-Lactate as a result of aerobic glycolysis, i.e., the processing ofglucose to lactate in the presence of physiological concentrations ofoxygen, upon synaptic stimulation to support neuronal function, providingthe first evidence of a lactate shuttle in the CNS (Pellerin and Magistretti,1994; Magistretti and Allaman, 2018). This metabolic profile of astrocytesand their role in brain energy metabolism was initially received withskepticism, as mammalian cells are known to generate their main energysource molecule, ATP, within mitochondria, starting from glucose. Indeed,since glucose is almost fully oxidized by the brain, this implied that atransfer of L-Lactate from astrocytes to neurons should exist. ATP ismainly produced by oxidative phosphorylation, fueled by the tricarboxylicacid (TCA) cycle. Pyruvate originating from the glycolysis is transformedin a sequence of reactions to produce substrates supporting the TCAactivity. Neurons are no different and express similar transporters forglucose (GLUT) at their membrane. Consistent with their high energeticdemands neurons are mainly oxidative (80%–90% of their metabolism;Magistretti and Allaman, 2015). Questions then arise, as to why shouldneurons behave differently, and somehow rely on astrocyte-derived lactateto support their energy needs? Is this metabolic profile due to the specificexpression of metabolic enzymes or because of the inability of neurons tostore energy in the form of glycogen (Magistretti and Allaman, 2018)?Also, how do astrocytes sustain neuronal metabolism? In this shortperspective article, we will briefly analyze these three points, and provide areview of recent evidence that address these questions.

TranscriptomeAnalysis(/articles/10.3389/fnmol.2018.00375/full)Michael B. Margineanu(https://loop.frontiersin.org/people/575187/overview), Hanan Mahmood(https://loop.frontiersin.org/people/599150/overview), Hubert Fiumelli(https://loop.frontiersin.org/people/605815/overview) and Pierre J.Magistretti(https://loop.frontiersin.org/people/1327/overview)

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References

11/16/19, 09:22Page 2 of 21

The Astrocyte Neuron Lactate Shuttle (ANLS)

According to the neuro-metabolism view up to the early ’90s, cells in theCNS simply need to consume glucose, whose constant supply needs to beprovided by the vascular system, in order to sustain the brain homeostasis.Indeed, as already demonstrated by Sherrington at the end of the 19thcentury, blood flow is coupled to neuronal activity through a mechanismknown as neurovascular coupling (Roy and Sherrington, 1890) mediatedby a variety of vasoactive molecules (Magistretti and Allaman, 2015). Thisactivity-dependent increase in local blood flow was considered sufficientto provide the necessary amount of glucose for the direct use by neurons.However, particularly upon intense neuronal activity, such as during longterm potentiation (LTP), when synaptic plasticity requires additionalenergy support, glucose does not seem to be the preferred substrate tomaintain neuronal activity (Suzuki et al., 2011). Experiments thatinvestigated learning and memory formation in the context of the energymetabolism have shown that lactate, rather than glucose, was effective inreversing the amnestic effect caused by the inhibition of monocarboxylatetransporters (MCTs) and of pharmacological inhibition of glycogenolysis,one of the mechanisms responsible for lactate production (Suzuki et al.,2011; Boury-Jamot et al., 2016; Gao et al., 2016). Supporting this view isthe “Astrocyte-Neuron Lactate Shuttle (ANLS),” a neuroenergetic modelfirst proposed in the ’90s, according to which glutamate uptake intoastrocytes as a result of synaptic activity triggers an intracellular signalingcascade within astrocytes that results in the production of L-Lactatethrough aerobic glycolysis (Pellerin and Magistretti, 1994).

The ANLS model reconciled, the morphological-based hypotheses ofCamillo Golgi related to astrocytic metabolic support of neurons, withexperimental evidence. In vivo experiments have demonstrated thatindeed astrocytes are the predominant site of glucose uptake duringsynaptic activity (Figure 1). Thus, downregulating the expression ofglutamate transporters on astrocytes drastically reduces the activity-dependent uptake of glucose into the brain parenchyma (Cholet et al.,2001; Voutsinos-Porche et al., 2003). A mirror experiment in which anincrease in glutamate transporters in astrocytes was inducedpharmacologically, resulted in an increase in glucose uptake into the brainparenchyma as determined by in vivo 2-deoxyglucose PET (Zimmer et al.,2017).

FIGURE 1

(https://www.frontiersin.org/files/Articles/442960/fncel-13-00082-HTML/image_m/fncel-13-00082-g001.jpg)Figure 1. Schematics of the peripheral vs. central action ofL-Lactate. Left, In the brain, neurons (blue) can uptakeglucose using glucose transporters (GLUTs) and use it as a

source of energy at the level of their soma. Around synapses, astrocytes (green) take up

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11/16/19, 09:22Page 3 of 21

glucose from the blood vessels (red) and store it as glycogen granules (black). Uponsynaptic activity, astrocytes produce L-Lactate in proximity of synapses, which expressmonocarboxylate transporter (MCT) transporters to import lactate as local source ofenergy. Lactate can also be formed from glycogen, the storage form of glucose. Right, Inperipheral tissues glucose fuels tricarboxylic acid (TCA) cycle via circulating lactatethrough glycolysis.

Additional in vivo experiments have shown that a gradient exists betweenthe concentration of L-Lactate in neurons and astrocytes, favoring itsefflux from astrocytes and its influx in neurons (Mächler et al., 2016), aphenomenon that has been also validated using computational models(Jolivet et al., 2015; Coggan et al., 2018).

Lactate is not only an energy substrate for neurons. Indeed, recentevidence, triggered by the observation that lactate transfer from astrocytesto neurons is necessary for LTP expression, synaptic plasticity andmemory consolidation (Suzuki et al., 2011) has shown that lactate is also asignaling molecule for synaptic plasticity. Indeed lactate modulates theexpression of at least 20 genes related to synaptic plasticity andneuroprotection (Yang et al., 2014; Margineanu et al., 2018). Thissignaling action of lactate is due to a positive modulation of N-Methyl-D-aspartate (NMDA) receptor signaling (Yang et al., 2014).

Glycogen

Recent findings about the specific role of lactate derived from glycogen,rather than direct glycolysis of glucose, represents another modalitythrough which the ANLS operates. Glycogen has a well-known structure,formed by linear chains of glucose that accumulates around a core proteincalled glycogenin, forming round granules of various size, between 20 and80 nm in diameter in astrocytic processes (Calì et al., 2016). Glycogen wasfirst discovered in peripheral tissues, and its concentration in the brain,compared to muscle and liver, is considerably lower, in a concentrationratio of 1:10:100, respectively (Magistretti and Allaman, 2013).Interestingly, glycogen granules are specifically located in astrocytes,although under pathological conditions they can accumulate in neurons,eventually to cause neurodegeneration, like in the Lafora disease (Mag-istretti and Allaman, 2007; Vilchez et al., 2007).

As glycogen is the storage form of glucose, it is safe to speculate about itsphysiological role as energy storage, which implies that astrocytes can beconsidered energy reservoirs. A pioneering work in the ’80s demonstratedhow, in the cortex, two neuromodulators, vasoactive intestinal peptide(VIP) and noradrenaline (NA; Magistretti et al., 1981; Magistretti andMorrison, 1988), are potent glycogenolytic signals, a phenomenonresulting in local increase of phosphate-bound energy sources (ATP)within the stimulated networks (Magistretti and Schorderet, 1984). Recentevidence confirms these findings, expanding our understanding of the roleof NA in particular, whose network activation is mobilized during

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11/16/19, 09:22Page 4 of 21

attentional states necessary for cognitive functions such as learning andmemory (Gao et al., 2016; Alberini et al., 2017). From a molecular point ofview, NA binds to β2 adrenergic receptors in astrocytes, whose activationtriggers glycogenolysis (Magistretti and Morrison, 1988; Sorg and Mag-istretti, 1992) and the subsequent rise of extracellular lactate levels thatare needed for LTP and memory formation (Suzuki et al., 2011; Gao et al.,2016).

Therefore, given the role of lactate derived from astrocytic glycogen insynaptic plasticity, a functional relationship between astrocytic processesfilled with glycogen and synaptic profiles is likely to exist (Calì et al., 2016,2017; Agus et al., 2018). Indeed, recent reports using 3D electronmicroscopy have shown the preferential location of glycogen granules inastrocytic processes around synapses, rather than being randomlydistributed in the astrocytic cytosol, both in the hippocampus and in thecortex (Calì et al., 2016; Mohammed et al., 2018). From an ultrastructuralpoint of view, such distribution suggests that when high firing rate resultsin phenomena like LTP, that are translated into higher functions such aslearning and memory stabilization, lactate, derived from glycogen storedwithin astrocytic granules close to synapses may exert its dual role of bothenergy substrate and signaling molecule for plasticity (Figure 1).

Sustained neuronal activity, like the one leading to LTP, does not merelyinduce a metabolic response in astrocytes, whose effect would bemeasurable after hours, but is also known to trigger an immediate calciumelevation (Araque et al., 2014; Bazargani and Attwell, 2016; Santello et al.,2019). Astrocytic calcium waves are diverse and complex (Di Castro et al.,2011; Agarwal et al., 2017; Bindocci et al., 2017), and their exact nature isstill under debate, although evidence has shown their role in triggeringglutamate release both in vitro and in situ (Bezzi et al., 1998). Onepotential mechanism involves exocytosis of synaptic-like microvesicles(Calì et al., 2008, 2009, 2014; Marchaland et al., 2008) upon activation ofastrocytic GPCRs (Bezzi et al., 2004). It is worth mentioning that in arecent report, astrocytes have been shown to modulate levels of anothermonamine, dopamine, in the prefrontal cortex (Petrelli et al., 2018). Theseastrocytes express channels and enzymes that regulate homeostasis ofdopamine, which could potentially modulate glycogen phosphorylase (GP)activity via cAMP (Smith et al., 2004). Furthermore, dopamine activationof D1-like receptors increases intracellular calcium levels, a mechanismlikely to take place in astrocytes. Despite the link between LTP andcalcium waves in astrocytes, a similar effect on metabolic substrates likelactate or glycogen is not known. A direct link has been reported betweenthe activation of the store-activated calcium channels (SOCE) in astrocytesand glycogenolysis. This process serves as a glycolytic source of ATP tofuel SERCA pumps, to maintain adequate calcium levels in ER stores(Müller et al., 2014). Calcium, in particular, is an indirect signal for GPactivation; therefore, one could speculate about the role of calcium inmobilizing energy stores in close proximity of microdomains. Conversely,calcium signaling in astrocytes might be affected by their metabolic

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turnover, as they depend on NAD+/NADH redox state, which is highlyinfluenced by lactate fluxes (Requardt et al., 2012; Wilhelm andHirrlinger, 2012).

Peripheral Lactate Utilization

The role of L-Lactate is not limited to the CNS. Metabolism in peripheraltissues, and the action of lactate have also been extensively investigated inskeletal muscle, heart and in tumoral tissues. Several groups identified thepresence of lactate dehydrogenase (LDH) on the mitochondria of spermcells (Hochachka, 1980) and then in kidney, liver and muscle cells (Klineet al., 1986; Brandt et al., 1987). Brooks (1985) first named the cell-to-celllactate shuttle in muscle, in 1985. Interestingly, the lactate shuttle is notlimited to cytoplasm-mitochondria communication but also to cytosol-peroxisome where it supports the β-oxidation (McClelland et al., 2003).Lactate is produced continuously under aerobic conditions in skeletalmuscle and oxidative muscle cells have the capacity to oxidize lactatepresent in the plasma or released by glycolytic muscle cells. It was alsoshown that rodent and human muscles cells possess the mitochondriallactate oxidation complex (mLOC; Dubouchaud et al., 2000) that includesthe presence of LDH isoforms, MCTs and cytochrome C oxidase, in theirmitochondria. Furthermore, lactate can also be oxidized by mitochondriaisolated from liver, heart and skeletal muscle cells.

During exercise, the oxidation of L-Lactate released by muscle cellsincreases up to 75%–80% of the basal values in the blood stream (Mazzeoet al., 1986) and it is now demonstrated that lactate can stimulatemitochondria biogenesis through activation of PGC1α (Hashimoto et al.,2007) which in turn influences the transcription of LDH isoforms toincrease the ratio of LDHA/LDHB. This change promotes the formation ofLactate over pyruvate (Summermatter et al., 2013). In the heart, duringexercise, it is also believed that lactate becomes the predominant source ofenergy compared to other metabolic sources (Gertz et al., 1988) andlongitudinal studies have demonstrated that trained animals have reducedlactate blood levels, most likely due to an enhanced capacity to use it as asubstrate by different organs (Bergman et al., 1999). Interestingly, itappears that during endurance exercise, significant amounts of brainderived neurotrophic factor (BDNF) are released in the bloodstreamcorrelating with the release of L-Lactate (Schiffer et al., 2011). BDNF is animportant trophic factor in the brain. L-Lactate has been demonstrated toincrease BDNF expression in different neural cell systems (Coco et al.,2013; Yang et al., 2014). Interestingly, recent work has shown that corticalastrocytes can recycle BDNF and ultimately promote TrkBphosphorylation, to sustain LTP (Vignoli et al., 2016).

Besides its role in brain and muscle physiology, lactate has an importantrole in cancer cells. Tumors have high glycolytic metabolism even undernormal O levels, a phenomenon known as the Warburg effect. Thisenvironment supports cancer cell survival and leads to accumulation of L-

2

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Lactate. This buildup has been reported to inhibit the migration of CD8+,CD4+ T-cells (Haas et al., 2015). Moreover, tumors producing high level ofLDHA (favoring the conversion of Pyruvate to Lactate) have less positiveoutcomes (Brand et al., 2016). Blood lactate concentration observedaround a tumorigenic environment can vary massively, raising from 1.5 to3 mM in physiological conditions, up to 30–40 mM in cancerous tissues(Hirschhaeuser et al., 2011; Colegio et al., 2014; Haas et al., 2015).Moreover, the inhibition of the immune system by L-Lactate is not limitedto a disturbance of immune cells metabolism, but also through an increaseof pro-survival factor such as HIF-1α or angiogenic factors (Shi et al.,2011; Magistretti and Allaman, 2018).

Overall, lactate has been shown to be involved in multiple processesbesides its metabolic support to muscle cells. L-Lactate ensures thesurvival of tumoral tissues by both promoting an environment favorablefor their growth and reducing the reactivity of the adaptive immunesystem.

Lactate as a Metabolic Bu!er Between Glucoseand Oxidative Metabolism in Peripheral Tissues

Recently a mechanism reminiscent of the ANLS has been shown tooperate at the whole-body level (Figure 1). Indeed using in vivo MagneticResonance Spectroscopy to trace the fate of various metabolites in fed andstarving mice, it was shown that C-lactate was extensively labeling TCAintermediates in peripheral organs (Hui et al., 2017). By measuringglucose metabolites in all organs, the authors found a considerably higheramount of circulating lactate compared to other metabolites, concludingthat L-Lactate can act as a reservoir molecule whose turnover can beglycolytically fine-tuned on demand, rather than directly using glucose.This mechanism is reminiscent of what is observed in tumorigenicenvironment, where circulating lactate represents a more efficient way touse local energy reserves and uncouple it from glucose availability, whichcan be influenced by multiple factors. Interestingly, the only exception wasthe brain, where glucose was surpassing the amount of circulating lactate.As shown by the ANLS, a lactate gradient between astrocytes and neurons(Mächler et al., 2016) allows its exchange via the MCTs. Such a metabolicflow relies on astrocytic glycolysis, which is necessarily coupled to glucoseutilization, triggered by synaptic signaling (Pellerin and Magistretti, 1994;Magistretti and Allaman, 2015). An even more tightly regulated way ofenergy delivery on demand occurs via lactate derived from glycogen(Suzuki et al., 2011; Gao et al., 2016). In this case, energy stores, under theform of glycogen granules, around synapses, can serve as metabolicreservoirs of lactate for energy delivery and plasticity signals for synapses.Consistent with the fact that astrocytes are locally synthesizing on demandlactate from glucose and glycogen, the amount of peripheral lactateaccessing the brain is minimal (Hui et al., 2017).

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From the above considerations, one should consider a dual action oflactate; one, as a source of energy, based on the uncoupling of glucosemetabolism from the TCA cycle in astrocytes and the delivery of lactate toneurons. The second one, via the glycogen, as a signaling molecule forplasticity.

Any Issues?

At its time of publication in 1994 (Pellerin and Magistretti, 1994), theANLS model has been challenged, although the concept of the lactateshuttle, at least in the skeletal muscle, was not a novelty (Brooks, 1985). Itis worth mentioning that most controversies around the ANLS raised fromcalculations inferred from theoretical models or metabolic stoichiometryrather than experimental data, opposing to the ANLS a modelhypothesizing lactate flow from neurons to astrocytes, for disposal into theblood stream. (Dienel, 2012, 2017) To summarize, the few opponents tothe ANLS argue that considering the rapid release of lactate in thebloodstream upon brain activity and the small concentration of lactate inthe brain its oxidation in the neurons cannot support their synapticactivity. However, a compelling number of in vivo investigations havedemonstrated that synaptic activity, and glutamate release triggerupstream intracellular cascades in astrocytes promoting glucose utilizationmainly by astrocytes (Chuquet et al., 2010; Jakoby et al., 2014). Moreover,experimental work has also shown that upon glutamate activity, theglycolytic activity in the astrocytes is enhanced, compared to neurons(Mongeon et al., 2016) and that the loss of astrocytic glutamatetransporters reduced the glucose consumption in activated brain areas(Cholet et al., 2001). Finally, some questions arose about the neuronaltype that can support the model. For example, since GABA uptake by theastrocytes does not trigger aerobic glycolysis (Peng et al., 1994; Chatton etal., 2003) it is clear that energy delivery to GABA neurons operatesthrough other mechanisms. However, since GABA neurons are mostlyinterneurons that are activated by glutamatergic inputs, it is conceivablethat the glutamate-stimulated ANLS may provide energy to GABAergicneurons. Overall, converging evidence from several laboratories indicatesthat the ANLS provides an operational model for the coupling betweenneurons and astrocytes (Barros and Weber, 2018).

Author Contributions

CC, AT and PM wrote the manuscript.

Funding

This work was supported by the CRG Grant No. 2313 from GlobalCollaborative Research, King Abdullah University of Science andTechnology “KAUST-EPFL Alliance for Integrative Modeling of Brain

11/16/19, 09:22Page 8 of 21

Energy Metabolism.”

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of anycommercial or financial relationships that could be construed as apotential conflict of interest.

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Keywords: glycogen, lactate, astrocyte, ANLS, synaptic plasticity

Citation: Calì C, Tau"enberger A and Magistretti P (2019) The Strategic Location of Glycogen and

Lactate: From Body Energy Reserve to Brain Plasticity. Front. Cell. Neurosci. 13:82. doi:

10.3389/fncel.2019.00082

Received: 19 December 2018; Accepted: 18 February 2019;

Published: 06 March 2019.

Edited by:

Marco Mainardi (https://loop.frontiersin.org/people/115988/overview), Scuola Normale Superiore

di Pisa, Italy

Reviewed by:

Gabriele Losi (https://loop.frontiersin.org/people/52015/overview), Institute of Neuroscience (IN),

Italy

Marina Guizzetti (https://loop.frontiersin.org/people/145313/overview), Oregon Health & Science

University, United States

Copyright © 2019 Calì, Tau"enberger and Magistretti. This is an open-access article distributed

under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommon-

s.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided

the original author(s) and the copyright owner(s) are credited and that the original publication in this

journal is cited, in accordance with accepted academic practice. No use, distribution or

reproduction is permitted which does not comply with these terms.

*Correspondence: Corrado Calì, corrado.cali@kaust.edu.sa (mailto:corrado.cali@kaust.edu.sa)

Arnaud Tau"enberger, arnaud.tau"enberger@kaust.edu.sa (mailto:arnaud.tau"enberger@kaust.e-

du.sa)

Pierre Magistretti, pierre.magistretti@kaust.edu.sa (mailto:pierre.magistretti@kaust.edu.sa)

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