The Role of Hypotheses in Current Research, Illustrated by Hypotheses on the Possible Role of Astrocytes in Energy Metabolism and Cerebral Blood Flow: From Newton to Now

Kimelberg, Harold K.

doi:10.1097/01.wcb.0000138668.10058.8c

Cited by 14 publications

(13 citation statements)

References 131 publications

(153 reference statements)

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“…Moreover, support for the hypothesis comes primarily from cultured cells rather than in vivo measurements (Kimmelberg, 2004). Subsequently, the ANLSH was modified to include just two ideas: glutamate uptake by astrocytes depends on anaerobic glycolysis, and neurons oxidize lactate produced by astrocytes .…”

Section: Effects Of Mct Inhibitionmentioning

confidence: 99%

“…In the current study, we used the respiratory effects of changes in extracellular pH (pHe) and intracellular pH (pHi) to test aspects of the astrocyte-neuronal lactate-shuttle hypothesis (ANLSH). Much of the support for the lactate-shuttle hypothesis comes from cultured cells (Kimmelberg, 2004), and we were therefore interested in testing the lactate shuttle hypothesis in vivo or in situ in brain slices. To that end, we first examined the ventilatory effects of focally inhibiting MCT2 in the RTN in vivo, and we measured pHe to determine whether inhibiting MCT2 altered pHe within the RTN.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Erlichman¹,

Hewitt²,

Damon³

et al. 2008

J. Neurosci.

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The astrocyte-neuronal lactate-shuttle hypothesis posits that lactate released from astrocytes into the extracellular space is metabolized by neurons. The lactate released should alter extracellular pH (pHe), and changes in pH in central chemosensory regions of the brainstem stimulate ventilation. Therefore, we assessed the impact of disrupting the lactate shuttle by administering 100 M ␣-cyano-4-hydroxycinnamate (4-CIN), a dose that blocks the neuronal monocarboxylate transporter (MCT) 2 but not the astrocytic MCTs (MCT1 and MCT4). Administration of 4-CIN focally in the retrotrapezoid nucleus (RTN), a medullary central chemosensory nucleus, increased ventilation and decreased pHe in intact animals. In medullary brain slices, 4-CIN reduced astrocytic intracellular pH (pHi) slightly but alkalinized neuronal pHi. Nonetheless, pHi fell significantly in both cell types when they were treated with exogenous lactate, although 100 M 4-CIN significantly reduced the magnitude of the acidosis in neurons but not astrocytes. Finally, 4-CIN treatment increased the uptake of a fluorescent 2-deoxy-D-glucose analog in neurons but did not alter the uptake rate of this 2-deoxy-D-glucose analog in astrocytes. These data confirm the existence of an astrocyte to neuron lactate shuttle in intact animals in the RTN, and lactate derived from astrocytes forms part of the central chemosensory stimulus for ventilation in this nucleus. When the lactate shuttle was disrupted by treatment with 4-CIN, neurons increased the uptake of glucose. Therefore, neurons seem to metabolize a combination of glucose and lactate (and other substances such as pyruvate) depending, in part, on the availability of each of these particular substrates.

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Section: Effects Of Mct Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Erlichman¹,

Hewitt²,

Damon³

et al. 2008

J. Neurosci.

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“…During the decade since the ANLS was first proposed, there has been continual debate over whether neuronal activity is fueled primarily by glucose or lactate. There have been a plethora of reviews written specifically to either support or refute the ANLS hypothesis, without any apparent consensus Chih and Roberts, 2003; Hertz, 2004;Kimelberg, 2004;Leybaert, 2005; Magistretti, 1994, 2003;Tsacopoulos and Magistretti, 1996). Although some of these recent reviews mention the glucose transporter (GLUT) proteins and the monocarboxylate transporter (MCT) proteins, little or no consideration has been given to the transport properties (capacity and affinity for substrates) of these transport systems and their relative contributions to substrate transport across the blood-brain barrier (BBB) and into the neural cells within the brain.…”

Section: Introductionmentioning

confidence: 99%

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

Simpson

Carruthers

Vannucci

2007

J Cereb Blood Flow Metab

703

749

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Glucose is the obligate energetic fuel for the mammalian brain, and most studies of cerebral energy metabolism assume that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter (GLUT) proteins deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood-brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters (MCT): MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, that is capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and -3 in BBB endothelial cells, astrocytes, and neurons, along with the corresponding kinetic properties of the MCTs, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed on neuronal activation. Keywords: glucose and lactate; glucose transporter proteins; mathematical modeling; monocarboxylate transporters; neurons and astrocytes; substrate delivery and metabolism IntroductionThe central dogma of cerebral energy metabolism is that glucose is the obligate energetic fuel of the mammalian brain and the only substrate able to completely sustain neural activity (Siesjo, 1978). Furthermore, it has traditionally been assumed that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state (Sokoloff et al, 1977). Rates of cerebral blood flow directly relate to measurements of cerebral oxygen consumption, generating the concept of the 'flow-metabolism couple' (Sokoloff, 1976;Sokoloff et al, 1977). The introduction of neuroimaging techniques to study cerebral metabolism revealed an 'uncoupling' between cerebral oxygen consumption, blood flow, and glucose utilization during brain activation (Fox and Raichle, 1986; Fox et al, 1988), with the suggestion of regional stimulation of oxidative glycolysis during neuronal activation. The temporal relationship between the release of lactate and the onset of neuronal activation, the source of the lactate, that is neuronal or glial, and its subsequent diffusion and disposal are all matters of considerable debate. Initial studies by Prichard et al (1991) assu...

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“…pyruvate as an energy source for neurons has not been fully clarified. It has been conjectured that increased synaptic activity stimulates glial metabolism and production of lactate that can be consumed by neurons [64,68] but simultaneously increased neuronal metabolism of glucose and lactate is probably not possible [65,66]. …”

Section: Investigations Of Two Metabolites As Treatments In Oxidatmentioning

confidence: 99%

Metabolomics of Oxidative Stress in Recent Studies of Endogenous and Exogenously Administered Intermediate Metabolites

Liu

Litt

Segal

et al. 2011

IJMS

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Aerobic metabolism occurs in a background of oxygen radicals and reactive oxygen species (ROS) that originate from the incomplete reduction of molecular oxygen in electron transfer reactions. The essential role of aerobic metabolism, the generation and consumption of ATP and other high energy phosphates, sustains a balance of approximately 3000 essential human metabolites that serve not only as nutrients, but also as antioxidants, neurotransmitters, osmolytes, and participants in ligand-based and other cellular signaling. In hypoxia, ischemia, and oxidative stress, where pathological circumstances cause oxygen radicals to form at a rate greater than is possible for their consumption, changes in the composition of metabolite ensembles, or metabolomes, can be associated with physiological changes. Metabolomics and metabonomics are a scientific disciplines that focuse on quantifying dynamic metabolome responses, using multivariate analytical approaches derived from methods within genomics, a discipline that consolidated innovative analysis techniques for situations where the number of biomarkers (metabolites in our case) greatly exceeds the number of subjects. This review focuses on the behavior of cytosolic, mitochondrial, and redox metabolites in ameliorating or exacerbating oxidative stress. After reviewing work regarding a small number of metabolites—pyruvate, ethyl pyruvate, and fructose-1,6-bisphosphate—whose exogenous administration was found to ameliorate oxidative stress, a subsequent section reviews basic multivariate statistical methods common in metabolomics research, and their application in human and preclinical studies emphasizing oxidative stress. Particular attention is paid to new NMR spectroscopy methods in metabolomics and metabonomics. Because complex relationships connect oxidative stress to so many physiological processes, studies from different disciplines were reviewed. All, however, shared the common goal of ultimately developing “omics”-based, diagnostic tests to help influence therapies.

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The Role of Hypotheses in Current Research, Illustrated by Hypotheses on the Possible Role of Astrocytes in Energy Metabolism and Cerebral Blood Flow: From Newton to Now

Cited by 14 publications

References 131 publications

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Inhibition of Monocarboxylate Transporter 2 in the Retrotrapezoid Nucleus in Rats: A Test of the Astrocyte–Neuron Lactate-Shuttle Hypothesis

Supply and Demand in Cerebral Energy Metabolism: The Role of Nutrient Transporters

Metabolomics of Oxidative Stress in Recent Studies of Endogenous and Exogenously Administered Intermediate Metabolites

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