Sugar for the brain: the role of glucose in physiological and pathological brain function

Abstract

The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We synthesize these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease.

Keywords: apoptosis; brain-body axis; glucose metabolism; metabolic brain disease; metabolic coupling.

Figure I. Example of a diagnostic [¹⁸F]fluoro-2-deoxyglucose 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 [103]. For visualtization, hyper- and hypometabolism is colour-coded across the entire brain as depicted in the legend. Images are from superior (top left) to inferior (bottom right). For details on the voxel-based statistical analysis to demonstrate hyper- and hypometabolism and the corresponding cohort study see Leypoldt et al. [103]. Images courtesy of Dr. R. Buchert, Charité.

Figure 1. 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.. (b) Glucose supply to the brain is regulated by neurovascular coupling and may be modulated by metabolism-dependent and -independent mechanisms. Glucose enters the brain from the blood by crossing the BBB through glucose transporter 1 (GLUT1), and (c) glucose and other metabolites (e.g. lactate, Lac) are rapidly distributed through a highly coupled metabolic network of brain cells. (d) Glucose provides the energy for neurotransmission, and (e) several glucose-metabolizing enzymes control cellular survival. Disturbed glucose metabolism on any of these levels can be the foundation for the development of a large variety of disorders of the brain (see section on “Disease mechanisms”).

Figure 2. 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. Hexokinase uses ATP to phosphorylate glucose to glucose-6-phosphate (Glc-6-P) in the first irreversible step of the glycolytic pathway. Glc-6-P regulates hexokinase activity by feedback inhibition [19], and it is a ‘branch-point’ metabolite that has alternative metabolic fates. Glc-6-P can continue down the glycolytic pathway to generate pyruvate that can then be used in mitochondria by oxidative metabolism via the tricarboxylic acid (TCA) cycle. It can also enter the pentose phosphate shunt pathway (PPP) to generate NADPH for management of oxidative stress and precursors for nucleic acid biosynthesis, and, in astrocytes, it is a precursor for glycogen. Most of the glucose carbon derived from the PPP re-enters the glycolytic pathway downstream of Glc-6-P. The glycolytic pathway produces a net of 2 ATP per molecule of glucose and oxidation of pyruvate via acetyl coenzyme A (acetyl CoA) in the TCA cycle produces about 30 ATP for a total of about 32 ATP. Formation of pyruvate from glucose requires regeneration of NAD⁺ from NADH produced by the glyceraldehyde-3-phosphate dehydrogenase reaction by the malateaspartate shuttle (MAS). NADH cannot cross the mitochondrial membrane, and the MAS transfers cytoplasmic NADH to the mitochondria where it is oxidized via the electron transport chain (ETC). When glycolytic flux exceeds that of the MAS or the TCA cycle rate, or during hypoxic or anoxic conditions, NAD⁺ is regenerated by the lactate dehydrogenase (LDH) reaction that converts pyruvate to lactate. Because intracellular accumulation of lactate would cause reversal of the LDH reaction, lactate must be released from the cell by monocarboxylic acid transporters (MCT). Exit of lactate eliminates pyruvate as an oxidizable substrate for that cell and limits the ATP yield per glucose to two. (b) Three models for the fate of lactate generated in brain from blood-borne glucose or astrocytic glycogen. The astrocyte-to-neuron lactate shuttle (ANLS) was proposed on the basis of glutamate-evoked increases in glucose utilization and lactate release by cultured astrocytes (reviewed in [29]). In brief, the model states that Na⁺-dependent uptake of neurotransmitter glutamate from the synaptic cleft by astrocytes generates a demand for 2 ATP in astrocytes, one to extrude Na⁺ and one to convert glutamate into glutamine in the glutamate-glutamine cycle (Glossary). The model states that this ATP is generated by the glycolytic pathway and is associated with release of lactate from astrocytes and its uptake by nearby neurons where it is oxidized. Thereby astrocyte-neuron metabolic coupling is linked with the glutamate-glutamine cycle and excitatory neurotransmission. Thus, during brain activation glycolytic upregulation is stated to occur in astrocytes, with astrocyte-derived lactate providing the major fuel for neurons. The neuron-toastrocyte lactate shuttle (NALS) is based on kinetics of glucose uptake into brain cells in response to increased metabolic demand and different model assumptions compared with the ANLS [27]. Here, glucose is predicted to be predominantly taken up into neurons due to their high energy demand and the higher transport rate of the neuronal glucose transporter, GLUT3, compared with the astrocytic glucose transporter, GLUT1 [16]. Lactate is posited to be generated by neurons and taken up by astrocytes. The lactate release model [5] is based on the observed mismatch between total glucose utilization and oxidative metabolism and measured lactate release from brain during brain activation in vivo. If lactate were produced and locally oxidized, total and oxidative metabolism would be similar in magnitude. However, the rise in oxidative metabolism varies with experimental condition and pathways stimulated, it is much less than that of total glucose utilization [5]. Astrocytes have a much faster and greater capacity for lactate uptake from extracellular fluid, and for lactate dispersal among gap junction-coupled astrocytes compared with neuronal lactate uptake and shuttling of lactate to neurons [17]. Astrocytic endfeet surround the vasculature, and can discharge lactate to perivascular fluid for efflux from brain.

Figure 3. The connection between glucose metabolism and cell death

(a) Glucose metabolism and cell death regulation intersect at several levels. Glucose metabolizing enzymes, including hexokinase II (HKII), glucokinase (GK), the fructose-2,6-bisphosphatase TIGAR (Tp53-induced Glycolysis and Apoptosis Regulator), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and others, are involved in the regulation of cell death through different mechanisms. Phosphoprotein-enriched in astrocytes (PEA15) might function as a molecular linker between HKII and TIGAR under certain conditions. Flux through the pentose phosphate pathway (PPP) generates NADPH, which is important for neuronal redox environment and inhibits cell death. (b) and (c) The expression of HKII in neurons is upregulated under hypoxic conditions. Together with PEA15 it functions as a molecular switch to regulate neuronal viability depending on the metabolic state [72]. HKII and PEA15 interact and bind to mitochondria through the outer-mitochondrial membrane voltage-dependent anion channel (VDAC). During hypoxia, HKII protects cells from cell death, whereas during glucose deprivation, where HKII detaches from mitochondria and the interaction with PEA15 is destabilized, HKII promotes cell death [72]. HKII also interacts with TIGAR under hypoxic conditions [77]. Similar to PEA15, which increases the capacity of HKII to protect neurons, TIGAR increases the glycolytic activity of HKII. However, the exact mechanistic link is presently unknown. Glc, glucose; GLUT, glucose transporter; Glc-6-P, glucose-6-phosphate; Fru-6-P, fructose-6-phosphate; Gal-3-P, glyceraldehyde-3-phosphate; Lac, lactate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; Pyr, pyruvate; TCA, tricarboxylic acid cycle; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane. HKII was rendered in Pymol using structure 2nzt (RCSB Protein Data Bank).