Glucose metabolic crosstalk and regulation in brain function and diseases
Introduction
Glucose is the primary energy source of the brain, which accounts for about 20 % of whole-body glucose consumption (Jais et al., 2016; Zhang et al., 2014). Alternate fuel sources supporting the brain include ketone bodies (acetoacetate, and β-hydroxybutyrate), lactate, fatty acids, and amino acids (valine, glutamine, leucine, isoleucine), which are primarily used in settings of limited glucose availability, such as fasting, starvation, and extended exercise (Fig. 1) (Bowman et al., 2019; Camandola and Mattson, 2017; Qi et al., 2019; Schönfeld and Reiser, 2017). Brain glucose metabolism can produce adenosine triphosphate (ATP) to fulfill complex neurological functions, including neuronal signaling transmission (action potentials, synaptic transmission, glutamate cycling, etc.), which consumes 70 % of the brain’s energy, and non-signaling activities (resting potentials, axonal transport, mitochondrial proton leak, oligonucleotide turnover, actin cytoskeleton remodeling, etc.), using 30 % of ATP produced from brain glucose metabolism (Fig. 1). Moreover, the carbon in the glucose structure can be transmitted to metabolites, such as pyruvate and glyceraldehyde-3-phosphate, which contribute to the synthesis of nucleic acids, fatty acids, and amino acids (Dienel, 2019). Glucose metabolism is also involved in oxidative stress modulation (NADH/NAD+ and NADP+/NADPH) (Fig. 1) (Dienel, 2019; Yu et al., 2018). A growing literature base shows that glucose metabolites and metabolism-related enzymes, such as hexokinase, acetyl-CoA, and glycolytic enzyme glyceradehyde-3-phosphate dehydrogenase, can also directly participate in cellular signaling and functional regulation (Li et al., 2018; Nakajima et al., 2015; Sivanand et al., 2018). For instance, lactate acts as a messenger modulating multiple molecular targets (hydroxycarboxylic acid receptor 1, acid-sensing ion channel, NADH/NAD+ ratio, ATP-sensitive potassium channel, etc.) (Barros, 2013). In addition, the reduced ratio of NADH and NAD+ resulting from glucose metabolism in microglia can suppress the inflammatory cascade (Shen et al., 2017). Therefore, glucose metabolites not only support ATP production and supply the carbon for macromolecule synthesis, but also modulate various functions of neurons and glial cells.
Glucose entrance into the brain is controlled by a family of specific glucose transporters (GLUTs) via facilitated diffusion, and it has been demonstrated that serum glucose levels can be five-fold higher than levels in the brain (Hwang et al., 2017, 2019). GLUT distribution in the vascular endothelial cells (ECs) of the blood-brain barrier (GLUT1), neurons (GLUT3,4,6,8), astrocytes (GLUT1,2), and microglia (GLUT 1, 3, 4, 5, 6, 8, 9, 10, 12, and 13) contribute to glucose transport from blood to cells in the brain (Fig. 2) (Wang et al., 2019a,2019b; Zhang et al., 2014), and GLUT-mediated glucose control is pivotal for cerebral metabolism.
The hypothalamus and pituitary play important roles maintaining blood glucose homeostasis, with some involvement of the cortex and striatum as well (Cheah and Amiel, 2012; Ter Horst et al., 2018). The glucose-sensing neurons of the brain, parasympathetic (vagus) and sympathetic nerves, and peripheral organs, such as the liver, muscles, intestines, and pancreas, work together to regulate whole-body glucose metabolism (Duncan et al., 2019; Soty et al., 2017; Steinbusch et al., 2015; Tan et al., 2020a). Additionally, insulin receptors are widely expressed in the cerebral cortex, hippocampus, hypothalamus, thalamus, choroid plexus and cerebellum (Fernandez and Torres-Alemán, 2012). Therefore, the brain plays an important role in regulating peripheral glucose metabolism. In turn, systemic metabolic disorders caused by high fat diets can decrease brain glucose uptake by downregulating GLUT1 expression on the vascular endothelial cells. This response can be countered by the compensatory production of vascular endothelial growth factor, which helps to block obesity-associated neurodegeneration (Jais et al., 2016). Ultimately, brain glucose metabolism and systemic glucose metabolism work in concert, and both brain and systemic metabolic disorders can contribute to the development of neurological disease.
Disturbances of glucose metabolism occur in the early stages of neurological disorders, catastrophically in stroke, and more subtly in Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Camandola and Mattson, 2017; Putzu et al., 2018). In the early reperfusion in a rat model of stroke, elevated glucose levels are observed in the infarct areas (Zhang et al., 2016). In the brain of AD patients and AD mouse models, glucose utilization is reduced, particularly in the brain regions most affected by the disease (Camandola and Mattson, 2017; Zhou et al., 2018b). Other evidence suggests that impaired glucose metabolism or disruption of cerebral insulin action contributes to the degeneration of neurons in AD (Camandola and Mattson, 2017; Kleinridders et al., 2014; Yan et al., 2020). Advances in methods for analyzing cell-type-specific features of glucose metabolism indicate that the metabolic alterations of glial cells strongly influence neuronal metabolism and regulate neurological function (Barros et al., 2018b), suggesting that metabolic coupling between neurons and glia is important for normal brain function and that alterations in such coupling may contribute to the pathogenesis of neurodegenerative disorders.
The present review provides an overview of the important technologies for studying brain glucose metabolism and illustrates progress and remaining challenges regarding the role of glucose metabolism in neurological diseases. We highlight the heterogeneity of glucose metabolism among different cell populations in the brain and how such cell type-specific features of glucose metabolism may affect neuronal vulnerability. We then consider the intercellular metabolic networks involved in brain glucose metabolism. Understanding these networks and their involvement in intercellular signaling may reveal novel approaches for preventing and treating neurological disorders.
Section snippets
Glucose metabolism for ATP generation
Cellular glucose is metabolized in the processes of glycolysis (including lactate production and oxidative phosphorylation), the pentose phosphate pathway (PPP), and glycogenesis (Fig. 3), which are critical to support cell function and energy storage (Mulukutla et al., 2016). Under the presence of adequate oxygen, glucose enters into the oxidative phosphorylation pathway, while 10–15 % of glucose is metabolized into carbon dioxide and water via an oxygen-independent process termed aerobic
Positron emission tomography (PET)
Fluorodeoxyglucose F18 (18F-FDG) is transported into brain tissue by GLUTs and is phosphorylated 18F-FDG-6-phosphate by HK. Because FDG is not further metabolized, it is then trapped in cells and can be measured for evaluating brain glucose uptake (Fig. 2B) (Izuishi et al., 2014). Thus, FDG-PET directly reflects cerebral glucose uptake, but not glucose metabolism. Several parameters impacting FDG transport between blood and brain may lead to changes in glucose uptake under pathological
Glucose metabolism in aging brain
Aging is a common risk factor for many neurological diseases. Multiple changes in glucose metabolism-related factors, such as glucose transport, mitochondrial function, DNA repair, and neurotrophic factors, contribute to aging in the brain (Camandola and Mattson, 2017). Aging neurons primarily rely on glucose oxidation via glycolysis, rather than astrocytic lactate support, as an energy source, and the enzymes of glycogen metabolism increase with aging in both astrocytes and neurons (
Glucose metabolism in neurologic diseases
Glucose metabolism plays a central role in maintaining brain cell viability and function and is also involved in the progress of multiple neurological diseases (Table 1). Chemical manipulation of the glucose metabolism pathway is promising for the development of new drugs to treat these diseases. Chemicals regulating glucose transportation or metabolism (Table 2) may become tools for experimental research and have the potential for clinical application.
Concluding remarks
The brain is composed of various specialized cell populations with distinct metabolic profiles, which contribute to region-specific metabolic features. Brain region-specific impairments of glucose metabolism have been characterized in ischemic brain injury, AD, PD, and HD. Ultimately, the development of a precise cell atlas of the brain and corresponding metabolic mapping will be critical for understanding the metabolism-based physiology and pathology of brain function.
Evidence has indicated
Author contributions
Shuai Zhang searched and reviewed literature, drafted the manuscript, and worked on the revision. Brittany Bolduc Lachance and Mark P. Mattson revised the manuscript. Xiaofeng Jia designed and formulated the review theme, viewed the literature, and revised and finalized the manuscript.
Declaration of Competing Interest
The authors declare no conflict of interests. The founding sponsors had no role in the writing of this review.
Acknowledgments
The work was supported by R01HL118084 and R01NS110387 from the National Institutes of Health (NIH) (both to X Jia). XJ was partially supported by NIH RO1 NS117102 (to XJ).
References (295)
- et al.
Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)-dependent glucose sensing to lower glucose production in high-fat-fed rats
J. Biol. Chem.
(2018) - et al.
Evidence for brain glucose dysregulation in Alzheimer’s disease
Alzheimers Dement.
(2018) - et al.
Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial
Lancet (London, England)
(2017) - et al.
Glucose consumption of inflammatory cells masks metabolic deficits in the brain
NeuroImage
(2016) - et al.
Astrocytic glycogen metabolism in the healthy and diseased brain
J. Biol. Chem.
(2018) Metabolic signaling by lactate in the brain
Trends Neurosci.
(2013)- et al.
Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation
Cell Metab.
(2011) - et al.
Glycolysis: a bioenergetic or a survival pathway?
Trends Biochem. Sci.
(2010) - et al.
Metabolic perturbations after pediatric TBI: it’s not just about glucose
Exp. Neurol.
(2019) - et al.
G6PD plays a neuroprotective role in brain ischemia through promoting pentose phosphate pathway
Free Radic. Biol. Med.
(2017)
Pyruvate kinase M2 increases angiogenesis, neurogenesis, and functional recovery mediated by upregulation of STAT3 and focal adhesion kinase activities after ischemic stroke in adult mice
Neurother.:J. Am. Soc. Exp. Neuro Ther.
TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes
Neuropharmacology
Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies
Prog. Neurobiol.
Brain glucose metabolism: role of Wnt signaling in the metabolic impairment in Alzheimer’s disease
Neurosci. Biobehav. Rev.
Activation of wnt signaling in cortical neurons enhances glucose utilization through glycolysis
J. Biol. Chem.
Beyond the redox imbalance: oxidative stress contributes to an impaired GLUT3 modulation in Huntington’s disease
Free Radic. Biol. Med.
FDG-PET imaging of dementia and neurodegenerative disease
Semin. Ultrasound CT MR
Analytical considerations for microdialysis sampling
Adv. Drug Deliv. Rev.
Brain insulin signalling, glucose metabolism and females’ reproductive aging: a dangerous triad in Alzheimer’s disease
Neuropharmacology
Dysregulation of glucose metabolism is an early event in sporadic Parkinson’s disease
Neurobiol. Aging
P2X7 receptor activation regulates microglial cell death during oxygen-glucose deprivation
Neuropharmacology
Astrocytic insulin signaling couples brain glucose uptake with nutrient availability
Cell
Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase in neurodegenerative processes and the role of low molecular weight compounds in counteracting its aggregation and nuclear translocation
Ageing Res. Rev.
Metabolic regulation of cell fate and function
Trends Cell Biol.
Metabolomics studies in brain tissue: a review
J. Pharm. Biomed. Anal.
Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study
Lancet Neurol.
Aerobic glycolysis in the human brain is associated with development and neotenous gene expression
Cell Metab.
Quality of evidence in studies evaluating neuroimaging for neurologic prognostication in adult patients resuscitated from cardiac arrest
Resuscitation
Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection
Am. J. Physiol. Cell Physiol.
Metabolic regulation of glial phenotypes: implications in Neuron-Glia interactions and neurological disorders
Front. Cell. Neurosci.
Astrocyte glycogen and lactate: new insights into learning and memory mechanisms
Glia
Glia as architects of central nervous system formation and function
Science
Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection
Proc. Natl. Acad. Sci. U. S. A.
Metabolic alterations induced by ischemia in primary cultures of astrocytes: merging 13C NMR spectroscopy and metabolic flux analysis
J. Neurochem.
Characterization of glucose-related metabolic pathways in differentiated rat oligodendrocyte lineage cells
Glia
Oligodendrocytes: development, physiology and glucose metabolism
Adv. Neurobiol.
Whiskers area as extracerebral reference tissue for quantification of rat brain metabolism using (18)F-FDG PET: application to focal cerebral ischemia
J. Nucl. Med.: Off. Publ. Soc. Nucl. Med.
A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease
Cell Metab.
Misconceptions regarding basic thermodynamics and enzyme kinetics have led to erroneous conclusions regarding the metabolic importance of lactate dehydrogenase isoenzyme expression
J. Neurosci. Res.
Current technical approaches to brain energy metabolism
Glia
Glia in brain energy metabolism: a perspective
Glia
Microglial metabolic flexibility supports immune surveillance of the brain parenchyma
Nat. Commun.
PARK2 mutation causes metabolic disturbances and impaired survival of human iPSC-Derived neurons
Front. Cell. Neurosci.
Impaired brain energy metabolism in the BACHD mouse model of Huntington’s disease: critical role of astrocyte-neuron interactions
J. Cereb. Blood Flow Metab.: Off. J. Int. Soc. Cereb. Blood Flow Metab.
Manganese acts upon Insulin/IGF receptors to phosphorylate AKT and increase glucose uptake in huntington’s disease cells
Mol. Neurobiol.
Mass spectrometry imaging: a review of emerging advancements and future insights
Anal. Chem.
MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c
J. Cereb. Blood Flow Metab.: Off. J. Int. Soc. Cereb. Blood Flow Metab.
Hypoxia-induced MicroRNA-212/132 alter blood-brain barrier integrity through inhibition of tight junction-associated proteins in human and mouse brain microvascular endothelial cells
Transl. Stroke Res.
Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
Sci. Rep.
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Nat. Rev. Neurosci.
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