In one model of PD, HKII, which regulates neuronal viability depending on the metabolic state [ 72 ] Figure 1e , has been suggested to inhibit degeneration of dopaminergic neurons [ ]. Disturbed metabolism in myelin-producing cells is associated with axonal degeneration. In the brain, defective lactate transporter levels in oligodendrocytes are linked to axonopathy [ 34 ] Figure 1c , and in the peripheral nervous system disrupted oxidative phosphorylation in Schwann cells is related to severe neuropathy [ 33 ].
However, demyelination without extensive axonal loss in an animal model of multiple sclerosis [ ] hints to a complex underlying mechanism. Autoantibodies against the NR1 subunit of the N-methyl-D-aspartate receptor NMDA-R may inhibit glutamatergic transmission Figure 1d by blocking, crosslinking, and initiating the internalization of the receptor.
The symptoms start with fever, psychosis, and seizures, and progress to abnormal movements, respiratory failure, dysautonomia, and coma [ ]. Despite these severe and long-lasting symptoms and changes in metabolism, most patients do not have pathological findings in diagnostic MRI-imaging studies. Furthermore, normalization in cerebral glucose metabolism accompanies recovery [ ]. Finally, disrupted central glucose sensing, insulin signaling, and defective hypothalamic circuits have been implicated in the pathophysiological mechanism of type 2 diabetes mellitus and obesity [ 49 , 59 , 62 - 64 , 67 ] Figure 1a.
At the same time, dysregulated glucose metabolism in diabetes mellitus can injure the brain through both hypo- and hyperglycemia [ ]. Furthermore, cachexia, a severe complication after cerebral ischemia, has been in part ascribed to dysregulation of the hypothalamus-pituitary-adrenal axis and perturbed efferent signaling [ ]. Given the role of hypothalamic structures for glucose and nutrient sensing see above and [ 49 , 51 ] , disturbed central glucose sensing and impeded central regulation of peripheral metabolism see above may contribute to the development of cachexia after CNS damage.
Glucose metabolism is closely integrated with brain physiology and function. Although recent studies have shed light on the complex regulation of biochemical, cellular, and systemic pathways, many features of the exact regulation remain controversial or elusive Box 3. The advent of novel and refined biochemical or genetic tools, screening methods, imaging technologies and systems analyses will allow for the study of cellular, subcellular, and even biochemical mechanisms in the cell or in vivo with unprecedented temporal and spatial resolution.
In addition to studying individual biochemical or cellular pathways and their control over intracellular signaling cascades e. Ultimately, a thorough understanding of these mechanisms will lead to better insight into the pathophysiology of multiple diverse disorders of the brain and allow the development of novel treatment strategies.
We are grateful to the members of our labs for their contribution to our underlying research. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
National Center for Biotechnology Information , U. Author manuscript; available in PMC Oct 1. Dienel , 3 and Andreas Meisel 1. Philipp Mergenthaler 1 Dept. Ute Lindauer 2 Experimental Neurosurgery, Dept. Andreas Meisel 1 Dept. The publisher's final edited version of this article is available at Trends Neurosci. See other articles in PMC that cite the published article. Abstract The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology.
Open in a separate window. The role of glucose for brain function Glucose Glc is the main source of energy for the mammalian brain, a Specialized centers in the brain, including proopiomelanocortin POMC and agouti-related peptide AgRP neurons in the hypothalamus, sense central and peripheral glucose levels and regulate glucose metabolism through the vagal nerve as well as neuroendocrine signals..
Glucose uptake in the brain — How are neurons and astrocytes fed?
Blood-brain barrier the permeability barrier arising from tight junctions between brain endothelial cells, restricting diffusion from blood to brain. Functional activation a response by the brain to a specific stimulus e. Glutamate-glutamine cycle the release of neurotransmitter glutamate from excitatory neurons, its sodium-dependent uptake by astrocytes, its conversion to glutamine by glutamine synthetase in astrocytes, release of glutamine and uptake into neurons followed by the conversion to glutamate by glutaminase and its repackaging into synaptic vesicles.
Hexokinase HK the enzyme catalyzing the first irreversible step in glucose metabolism, the irreversible conversion of glucose to glucosephosphate GlcP in an ATP-dependent reaction. Metabolic coupling a synergistic interaction between different cells or cell types in which compounds produced in one cell are used by another cell.
Neurovascular unit groups of neurons, astrocytes, endothelial cells, vascular smooth muscle cells and pericytes that are involved in local signaling activities, metabolic interactions, and regulation of blood flow.
Glucose Metabolism in the Brain, Volume 51 (International Review of Neurobiology): Medicine & Health Science Books @ Amazon. com. linawycatuzy.gq: Glucose Metabolism in the Brain (International Review of Neurobiology, 51): Donard Dwyer.
Generation of energy in brain and three models for the fate of lactate derived from glucose metabolism in the brain a Major pathways of glucose metabolism. Metabolic interactions among astrocytes and neurons and lactate shuttling Both neurons [ 16 , 27 , 28 ] and astrocytes [ 18 , 29 ] have been described as the main consumers of glucose. Glucose metabolism and the regulation of cerebral blood flow Under resting conditions, local CBF is highest in brain regions with the highest local glucose metabolism. Brain-body axis — central control over peripheral glucose metabolism Given that the brain relies on exogenous nutrient supplies, it is not surprising that the brain can increase these supplies, especially glucose, by regulating systemic homeostasis and food intake [ 49 , 50 ] Figure 1a.
The connection between glucose metabolism and cell death a Glucose metabolism and cell death regulation intersect at several levels. Disease mechanisms Neurons are largely intolerant of inadequate energy supply, and thus the high energy demand of the brain predisposes it to a variety of diseases if energy supplies are disrupted.
Box 1 Glucose metabolism and functional brain imaging: Example of a diagnostic [ 18 F]fluorodeoxyglucose PET-CT As illustrated in this 23 year-old female patient after a two-month course of severe anti-NMDA-R encephalitis, these patients typically show widespread frontotemporal cortical hypermetabolism as well as bioccipital and cerebellar cortical hypometabolism [ ]. Box 2 Glucose metabolism, cell death and neurodegeneration Glucose metabolism and the regulation of cell death are tightly coupled [ 66 , 71 , 72 ] Figure 3.
Autophagy can be activated upon metabolic stress e. Autophagy, in turn, can be regulated by cell death and metabolic pathways [ 61 ], including key regulators of glucose metabolism [ 78 ]. Defective autophagy, oxidative stress and bioenergetic stress have been linked to the development of neurodegenerative diseases [ 61 , 96 , ]. Disrupted axonal nutrient supply and a defective metabolic network are associated with neurodegeneration in the central and peripheral nervous system [ 33 , 34 ]. Future research will elucidate the role of defective glucose metabolism and the extent of the involvement of members of the glycolytic cascade [ 72 , 76 - 78 ] in the pathophysiology of neurodegenerative diseases.
Concluding remarks Glucose metabolism is closely integrated with brain physiology and function. Box 3 Outstanding questions Does modeling accurately predict actual energy use of the brain? Can metabolic substrates be interchanged? Are there functional consequences of using glucose and other metabolites respectively? Future studies need to address the consequences of oxidative vs. What metabolic substrates support neurons and other cell types under different functional states of the brain? What is the relevance of shuttling of metabolic substrates between different cell types? Does the direction of metabolic shuttling between cells depend on the physiological or experimental context?
How does metabolic coupling among brain cells and shuttling of metabolites sustain brain activity? Are there additional anatomical or cellular networks in the brain which control peripheral glucose metabolism? Do cell death pathways contribute to central glucose sensing? How does disturbed peripheral metabolism influence central glucose sensing and regulation? How does disrupted central glucose sensing cause systemic metabolic disorders?
What is the functional connection in the regulation of cell death pathways through different members of the glycolytic cascade? What is the functional impact of this connection for different cells of the brain e. How does dysbalanced metabolism and subsequent dysregulation of cell death pathways contribute to neurodegenerative diseases or other acute or chronic disorders of the brain? How can knowledge about cerebral glucose metabolism be exploited for refined therapies of neurodegenerative disorders or other diseases of the brain?
We provide a comprehensive overview of the role of glucose metabolism for normal brain function. Acknowledgements We are grateful to the members of our labs for their contribution to our underlying research. Howarth C, et al. Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb Blood Flow Metab. Erbsloh F, et al. Harris JJ, et al. Synaptic energy use and supply. Ivannikov MV, et al.
Calcium clearance and its energy requirements in cerebellar neurons. Fueling and imaging brain activation. Hertz L, Gibbs ME. What learning in day-old chickens can teach a neurochemist: Suzuki A, et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Lauritzen KH, et al.
Bergersen LH, Gjedde A. Is lactate a volume transmitter of metabolic states of the brain? Alle H, et al. Energy-efficient action potentials in hippocampal mossy fibers.
Furthermore, lactate is preferred over glucose if both these substances are available. See FREE shipping information. In essence, the brain increases its utilization of glucose upon activation [ 13 ]. Astrocytes, on one hand, can communicate with capillaries, and on the other are associated with neurons and synaptic processes. However, this notion remains controversial because glutamate does not stimulate glycolysis in most astrocyte preparations, the cellular origin of lactate in vivo is unknown, substantial lactate oxidation by neurons has not been demonstrated during brain activation, and studies supporting this model [ 29 ] have been challenged [ 5 , 22 ].
Liotta A, et al. Energy demand of synaptic transmission at the hippocampal Schaffer-collateral synapse. Harris JJ, Attwell D. The energetics of CNS white matter. Energetics of functional activation in neural tissues.
Blood lactate is an important energy source for the human brain. Lutas A, Yellen G. Simpson IA, et al. Supply and demand in cerebral energy metabolism: Gandhi GK, et al. Astrocytes are poised for lactate trafficking and release from activated brain and for supply of glucose to neurons. Rouach N, et al. Astroglial metabolic networks sustain hippocampal synaptic transmission.
Isozymes of mammalian hexokinase: Borgstrom L, et al. Glucose consumption in the cerebral cortex of rat during bicuculline-induced status epilipticus. Lowry OH, et al. Dienel GA, et al. A glycogen phosphorylase inhibitor selectively enhances local rates of glucose utilization in brain during sensory stimulation of conscious rats: Walls AB, et al. Robust glycogen shunt activity in astrocytes: Effects of glutamatergic and adrenergic agents. Dinuzzo M, et al. The role of astrocytic glycogen in supporting the energetics of neuronal activity. Hyder F, Rothman DL. Quantitative fMRI and oxidative neuroenergetics.
Mangia S, et al. Hall CN, et al. Oxidative phosphorylation, not glycolysis, powers presynaptic and postsynaptic mechanisms underlying brain information processing. Pellerin L, Magistretti PJ. Sweet sixteen for ANLS. Bauer DE, et al. The glutamate transporter, GLAST, participates in a macromolecular complex that supports glutamate metabolism.
Astrocytic energetics during excitatory neurotransmission: What are contributions of glutamate oxidation and glycolysis? Newman LA, et al.
Lactate produced by glycogenolysis in astrocytes regulates memory processing. Funfschilling U, et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Lee Y, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Overgaard M, et al. Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain. Fox PT, et al. Nonoxidative glucose consumption during focal physiologic neural activity.
Devor A, et al. Stimulus-induced changes in blood flow and 2-deoxyglucose uptake dissociate in ipsilateral somatosensory cortex. On the Regulation of the Blood-supply of the Brain. Attwell D, et al. It performs a tremendous position in illnesses corresponding to diabetes, stroke, schizophrenia and drug abuse in addition to in common and dysfunctional reminiscence and cognition. This quantity represents an intensive exam of all of the significant matters which are proper to glucose metabolism through mind cells when it comes to sickness, combining easy examine and scientific findings in one, necessary reference.
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