Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism

Abstract

Aerobic glycolysis occurs during brain activation and is characterized by preferential up-regulation of glucose utilization compared with oxygen consumption even though oxygen level and delivery are adequate. Aerobic glycolysis is a widespread phenomenon that underlies energetics of diverse brain activities, such as alerting, sensory processing, cognition, memory, and pathophysiological conditions, but specific cellular functions fulfilled by aerobic glycolysis are poorly understood. Evaluation of evidence derived from different disciplines reveals that aerobic glycolysis is a complex, regulated phenomenon that is prevented by propranolol, a non-specific b-adrenoceptor antagonist. The metabolic pathways that contribute to excess utilization of glucose compared with oxygen include glycolysis, the pentose phosphate shunt pathway, the malate-aspartate shuttle, and astrocytic glycogen turnover. Increased lactate production by unidentified cells, and lactate dispersal from activated cells and lactate release from the brain, both facilitated by astrocytes, are major factors underlying aerobic glycolysis in subjects with low blood lactate levels. Astrocyte-neuron lactate shuttling with local oxidation is minor. Blockade of aerobic glycolysis by propranolol implicates adrenergic regulatory processes including adrenal release of epinephrine, signaling to brain via the vagus nerve, and increased norepinephrine release from the locus coeruleus. Norepinephrine has a powerful influence on astrocytic metabolism and glycogen turnover that can stimulate carbohydrate utilization more than oxygen consumption, whereas breceptor blockade 're-balances' the stoichiometry of oxygenglucose or -carbohydrate metabolism by suppressing glucose and glycogen utilization more than oxygen consumption. This conceptual framework may be helpful for design of future studies to elucidate functional roles of preferential nonoxidative glucose utilization and glycogen turnover during brain activation. Keywords: aerobic glycolysis, astrocyte, epinephrine, glycogen, lactate, norepinephrine. J. Neurochem. (2016) 138, 14-52.This review first describes characteristics of aerobic glycolysis, and then identifies metabolic pathways that contribute to its becoming manifest with increases in their rates. Lactate release is recognized as a major, but not the only, factor in causing greater utilization of glucose than oxygen during brain activation. Astrocytes have a high impact on the phenomenon because of glycogen turnover, lactate dispersal through gap junctions, and lactate discharge from the brain. Aerobic glycolysis is prevented by propranolol, a non-specific b-adrenoceptor antagonist, implicating adrenergic signaling in regulation of the cellular activities that contribute to aerobic glycolysis. Analysis of studies in diverse fields ranging from metabolic assays of brain activation to memory consolidation led to a model describing adrenergic regulation of aerobic glycolysis. The model posits that stress-related Abbreviations used: AGC, aspartate-gl...

‘SNO’-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders

“…Additionally, genetic manipulation studies suggested a physiological role of metabolic neuron-glia coupling in intact mice and drosophila [29–31]. However, the physiological role of the ANLS in brain energetics is still under scrutiny [32]. Future studies are warranted to evaluate actual lactate transport rates in vivo .…”

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“…The brain’s utilization of glucose exceeds that predicted from the rate of oxygen consumption (Boyle et al, 1994; Dienel and Cruz, 2016; Madsen et al, 1995; Vaishnavi et al, 2010). Such mitochondrial-independent glucose consumption varies regionally, developmentally, and according to neuronal activity (Goyal et al, 2014; Madsen et al, 1995; Settergren et al, 1976; Vaishnavi et al, 2010), and reflects ‘aerobic glycolysis’ and pentose phosphate pathway (PPP) activities.…”

Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients

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“…For example, glutamate-evoked lactate release is not a robust phenotype of cultured astrocytes, glutamate is oxidized by cultured astrocytes to generate more ATP than glycolysis, lactate oxidation coupled with glycolysis requires a parallel rise in CMR O2 with CMR glc during brain activation that does not occur (i.e., OGI falls during brain activation), and lactate oxidation would cause trapping of labeled metabolites of glucose to the same extent as the rise in glycolytic rate, which does not occur during brain activation. 20 For these reasons, lactate shuttling and utilization have been a controversial issue. [45][46][47][48][49][50][51][52][53][54] Importantly, in vitro studies have shown that lactate can maintain ATP levels but not sustain neuronal signaling, underscoring unidentified but critical roles of glucose metabolism upstream of pyruvate/lactate for neuronal function.…”

“…upregulation of non-oxidative metabolism. 20 Lactate metabolism is taken into account with the oxygen-carbohydrate index (OCI ¼ CMR O2 /(CMR glc þ 0.5CMR lac ), where 0.5CMR lac represents CMR glc equivalents (1 glucose ¼ 2 lactate). Energetics or neuroenergetics involves generation and utilization of ATP for energy-dependent processes ( Figure 3).…”