A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: implications for glycogen turnover

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165

Glycogen is present in the brain, where it has been found mainly in glial cells but not in neurons. Therefore, all physiologic roles of brain glycogen have been attributed exclusively to astrocytic glycogen. Working with primary cultured neurons, as well as with genetically modified mice and flies, here we report that-against general belief-neurons contain a low but measurable amount of glycogen. Moreover, we also show that these cells express the brain isoform of glycogen phosphorylase, allowing glycogen to be fully metabolized. Most importantly, we show an active neuronal glycogen metabolism that protects cultured neurons from hypoxia-induced death and flies from hypoxia-induced stupor. Our findings change the current view of the role of glycogen in the brain and reveal that endogenous neuronal glycogen metabolism participates in the neuronal tolerance to hypoxic stress.

Section: Discussionsupporting

confidence: 57%

Neurons Have an Active Glycogen Metabolism that Contributes to Tolerance to Hypoxia

Sáez

Durán

Sinadinos

et al. 2014

178

165

“…b Extracellular fluid (ECF) brain glucose level is from Hu and Wilson (1997a) who used the same glucose sensor and experimental paradigm as did Hu and Wilson (1997b); absolute values for extracellular lactate were estimated as follows. Values for total brain tissue lactate level in various regions of normal resting rat brain range from B0.2 to 0.6 mmol/g in our laboratory (Dienel et al, , 2007aCruz and Dienel, 2002); similar percentage increases also occur in the human brain (Mangia et al, 2007b). To allow for higher interlaboratory values up to B1 mmol/g, an intermediate value for resting brain [lac] = 0.75 was used for calculations in this table.…”

Section: Glucose-sparing Action Of Alternative Substrates That Increasupporting

confidence: 54%

“…The quantity of lactate that accumulates in the brain during an activation episode is < 5% of the pyruvate formed from glucose (Dienel et al, 2007a). The lactate level in a normal resting brain is linearly related to that of pyruvate (Dienel and Cruz, 2008), and its increase (Siesjö , 1978), and metabolic assays using high, flooding doses of lactate (greater than B3 mmol/L) mimic brain pathology or physically active subjects.…”

Section: Lactate Concentration and Utilization Ratesmentioning

confidence: 99%

Brain Lactate Metabolism: The Discoveries and the Controversies

Dienel

2011

416

434

Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-toblood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. Keywords: astrocyte; brain activation; glucose; lactate shuttling; metabolism; neuron Glucose is the major fuel for the brain, and its metabolism by different pathways has important functions related to energetics, neurotransmission, oxidation-reduction (redox) reactions, and biosynthesis of essential brain components (Figure 1). For many decades, lactate production in the brain was viewed as a consequence of inadequate oxygen delivery, disruption of oxidative metabolism, or mismatch between glycolytic and oxidative rates (Siesjö, 1978), but more recently, the conceptual role of lactate metabolism and function in the normal brain have undergone major changes, shifting from developmental fuel and glycolytic waste product to include its use as a supplemental fuel and signaling molecule. Starting in the 1970s to 1980s studies carried out in different laboratories with diverse experimental interests related to brain function brought attention to upregulation of glycolysis, lactate production, lactate release into the blood, the possibility of lactate shuttling among cell types within the brain, lactate fueling adult brain during exercise, and roles of lactate in the regulation of blood flow; some of these topics are controversial and highly debated. The experimental paradigm and physiologic status of subjects are critical for interpretation of data, and this review first presents a brief historical overview of studies related to brain lactate transport and metabolism, then compares sets of data to provide a perspective and context within which the consistency of simi...

“…Nevertheless, glycogenolysis also occurs in euglycemia during an increase in neuronal activity, indicating that brain glycogen also has a role in supporting neuronal function in nonpathologic condition. [1][2][3][4] In this regard, glycogen concentration seems to be more conspicuous in areas of high synaptic density. 5,6 It has been proposed that the importance of brain glycogen lies in the rapidity of its breakdown compared with the uptake of extracellular glucose.…”

Section: Introductionmentioning

confidence: 95%

Impairment in Long-Term Memory Formation and Learning-Dependent Synaptic Plasticity in Mice Lacking Glycogen Synthase in the Brain

Durán

Sáez

Gruart

et al. 2013

132

127

Glycogen is the only carbohydrate reserve of the brain, but its overall contribution to brain functions remains unclear. Although it has traditionally been considered as an emergency energetic reservoir, increasing evidence points to a role of glycogen in the normal activity of the brain. To address this long-standing question, we generated a brain-specific Glycogen Synthase knockout (GYS1 Nestin-KO ) mouse and studied the functional consequences of the lack of glycogen in the brain under alert behaving conditions. These animals showed a significant deficiency in the acquisition of an associative learning task and in the concomitant activity-dependent changes in hippocampal synaptic strength. Long-term potentiation (LTP) evoked in the hippocampal CA3-CA1 synapse was also decreased in behaving GYS1 Nestin-KO mice. These results unequivocally show a key role of brain glycogen in the proper acquisition of new motor and cognitive abilities and in the underlying changes in synaptic strength.