Noradrenaline enhances monocarboxylate transporter 2 expression in cultured mouse cortical neurons via a translational regulation

Pierre, Karin; Debernardi, Ruth; Magistretti, Pierre J.; Pellerin, Luc

doi:10.1046/j.1471-4159.2003.01964.x

Cited by 49 publications

(47 citation statements)

References 53 publications

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“…The recent confirmation of MCT2 being predominantly expressed in neurons whereas MCT1 and MCT4 are found instead in astrocytes is consistent with distinct roles in these two cell types (Bergersen et al, 2002;Debernardi et al, 2003;Pierre et al, 2002). Of course, it can not be concluded from the simple distribution of these isoforms that lactate is shuttled from one cell type to the other.…”

Section: Monocarboxylate Transporters: What Where and Why?mentioning

confidence: 86%

Food for Thought: Challenging the Dogmas

Pellerin

Magistretti

2003

J Cereb Blood Flow Metab

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171

137

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For years, the field of brain energy metabolism has been dominated by the concept that glucose was the sole energy substrate used by adult brain cells to sustain neural activity (Sokoloff, 1989). Moreover, it was determined from oxygen consumption and carbon dioxide production rates that the respiratory quotient of the brain is close to 1, indicating that oxidative phosphorylation was by far the predominant process to generate energy in the central nervous system. Because the ratio of O 2 /glucose use is near 6.0, almost complete oxidation of glucose takes place to provide most of the energy needed by the brain, leaving relatively little importance to other pathways. With time, these statements have been raised to the status of central dogma of brain energy metabolism and have remained almost undisputed ever since, despite episodic reports of putative exceptions. Part of this situation could be explained by the stunning success of the 2-deoxyglucose autoradiography technique that was later adapted for human brain imaging with the advent of positron emission tomography (PET). Application of this new tool to explore brain functions also led to a relative disinterest in the fundamental features of brain energy metabolism, with the assumption that the previously established principles safely form the unquestionable basis upon which these newly emerging brain imaging techniques can rely.A first set of studies that questioned these relationships among brain metabolic parameters came from the imaging field rather than from neurochemists and, more specifically, from the group of Marcus Raichle at Washington University (Fox and Raichle, 1986;Fox et al., 1988). From parallel measurements of blood flow changes, glucose use and oxygen consumption by PET in humans, Raichle and colleagues observed an uncoupling between oxygen consumption on one hand and glucose use or blood flow changes on the other. These observations were interpreted as evidence for a predominant enhancement of glycolysis in activated areas that would provide the energy necessary for neuronal activity.

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Section: Monocarboxylate Transporters: What Where and Why?mentioning

confidence: 86%

Food for Thought: Challenging the Dogmas

Pellerin

Magistretti

2003

J Cereb Blood Flow Metab

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171

137

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“…Several downstream sources of purine metabolism, such as AMP, inosine, IMP, hypoxanthine, and uric acid, were increased in both the muscle and brain of exercise-exhausted animals. Although the mechanisms for increases in MCT2 protein are unclear, noradrenaline (NA) is an activator not only for astrocytic glycogenolysis (36) but also for MCT2 expression in neurons (37). NA neurons are activated during prolonged exercise (14).…”

Section: Discussionmentioning

confidence: 99%

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Matsui

Omuro

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

122

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Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresismass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxycinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.brain glycogen | lactate transport | ATP | endurance capacity | metabolomics G lucose derived from blood is the primary energy source for generating ATP in the brain, but an important energy reserve is brain glycogen synthesized from glucose in astrocytes (1). Astrocytic glycogen is broken down through glycogenolysis/glycolysis to produce lactate as a neuronal energy substrate transported by monocarboxylate transporters (MCTs) (2). Indeed, brain glycogen decreases during memory tasks (3) and in some physiologically exhaustive conditions such as sleep deprivation (4) and hypoglycemia (5). The genetic/pharmacologic inhibitions of glycogenolysis and/or lactate transport impair neuronal survival under severe hypoglycemia, as well as axon transmission and hippocampus-related memory formation (6-8). Therefore, astrocytic glycogen-derived lactate is a critical energy source for meeting brain energy demands for neuronal functions and/or survival.Although less than for exercising muscles, physical exercise activates brain neurons and increases brain energy demand (9). Blood glucose and lactate contribute to brain energetics during moderate or intense exercise (10, 11). Muscle glycogen is an important energy for maintaining muscle contraction during endurance ex...

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“…In this context, over the years our laboratory has gathered evidence that plasticity of energy metabolism is regulated by a restricted set of neurotransmitters. Such adaptations in metabolic pathways are mediated by transcriptional mechanisms that modulate the expression of genes involved in energy metabolism (Allaman et al, 2003;Allaman et al, 2000;Allaman et al, 2004;Debernardi et al, 2003;Pierre et al, 2003;Sorg and Magistretti, 1992). Most of the data on metabolic plasticity that our laboratory has collected relate to in vitro analyses at the molecular level.…”

Section: Synaptic Plasticity and Metabolic Plasticitymentioning

confidence: 99%

Neuron–glia metabolic coupling and plasticity

Magistretti

2006

Journal of Experimental Biology

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608

399

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Brain energy metabolismBackground The energy requirements of the brain are amazingly high; indeed, while representing only 2% of the body mass, its oxygen and glucose utilization account for approximately 20% of those of the whole organism, almost ten times more than those predicted on a mass basis . A similar mismatch is observed for blood flow destined to the brain, which represents over 10% of cardiac output. In addition to these quantitative aspects, brain metabolism has other distinctive features, in particular its regional variability and the nature of its cellular determinants. At the macroscopic level, one regional variability is manifested by the difference in energy metabolism between grey and white matter (Clarke and Sokoloff, 1994). But a much finer feature of brain metabolism is that its regional variability is strongly determined by the ever-changing spatially and temporally specified levels of synaptic activity. Thus one of the founding principles of brain physiology is that metabolism and flow are tightly coupled with neuronal activity; this fact has been appreciated since the turn of the 19th century when Sherrington proposed that "…the brain possess an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations of functional activity" (Roy and Sherrington, 1890).The pioneering work of Louis Sokoloff and his colleagues in the 1970s and 1980s using the 2-deoxyglucose (2-DG) autoradiographic technique and its in vivo extension to humans with 18-fluoro-DG imaging of glucose utilization by positron emission tomography (PET) (Sokoloff et al., 1977), has clearly demonstrated a similar coupling between neuronal activity and glucose metabolism. Indeed, this tight relationship between neuronal activity with blood flow and metabolism has provided the basis for the functional brain imaging techniques that are now widely in use by cognitive neuroscientists and clinicians (Mazziotta et al., 2000). Thus local changes in glucose utilization, blood flow and oxygen utilization for PET and, mostly, variations in the level of hemoglobin oxygenation for functional magnetic resonance imaging (fMRI) during wellThe coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiological principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography (PET). Astrocytes play a central role in neurometabolic coupling, and the basic mechanism involves glutamate-stimulated aerobic glycolysis; the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase triggers glucose uptake and processing via glycolysis, resulting in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fuelling of the neuronal energy demands associated with synaptic transmission. An operational model, the 'astrocyteneuron lactate shuttle', is supported experimentally by a large body of evidence, which provides a molecu...

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Noradrenaline enhances monocarboxylate transporter 2 expression in cultured mouse cortical neurons via a translational regulation

Cited by 49 publications

References 53 publications

Food for Thought: Challenging the Dogmas

Food for Thought: Challenging the Dogmas

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Neuron–glia metabolic coupling and plasticity

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