Neuronal Glucose Metabolism Research Articles

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD), and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression. Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid-beta 42 and tau oligomers, two major pathological effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner. Conversely, pharmacological IDO1 inhibition restores glycolysis and lactate production. In amyloid-producing APP Swe -PS1 ΔE9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition restores spatial memory and improves hippocampal glucose metabolism by metabolomic and MALDI-MS analyses. IDO1 blockade also rescues hippocampal long-term potentiation (LTP) in a monocarboxylate transporter (MCT)-dependent manner, suggesting that IDO1 activity disrupts astrocytic metabolic support of neurons. Indeed, in vitro mass-labeling of human astrocytes demonstrates that IDO1 regulates astrocyte generation of lactate that is then taken up by human neurons. In co-cultures of astrocytes and neurons derived from AD subjects, deficient astrocyte lactate transfer to neurons was corrected by IDO1 inhibition, resulting in improved neuronal glucose metabolism. Thus, IDO1 activity disrupts astrocytic metabolic support of neurons across both amyloid and tau pathologies and in a model of AD iPSC-derived neurons. These findings also suggest that IDO1 inhibitors developed for adjunctive therapy in cancer could be repurposed for treatment of amyloid- and tau-mediated neurodegenerative diseases.

WNKs regulate mouse behavior and alter central nervous system glucose uptake and insulin signaling.

Certain areas of the brain involved in episodic memory and behavior, such as the hippocampus, express high levels of insulin receptors and glucose transporter-4 (GLUT4) and are responsive to insulin. Insulin and neuronal glucose metabolism improve cognitive functions and regulate mood in humans. Insulin-dependent GLUT4 trafficking has been extensively studied in muscle and adipose tissue, but little work has demonstrated either how it is controlled in insulin-responsive brain regions or its mechanistic connection to cognitive functions. In this study, we demonstrate that inhibition of WNK (With-No-lysine (K)) kinases improves learning and memory in mice. Neuronal inhibition of WNK enhances in vivo hippocampal glucose uptake. Inhibition of WNK enhances insulin signaling output and insulin-dependent GLUT4 trafficking to the plasma membrane in mice primary neuronal cultures and hippocampal slices. Therefore, we propose that the extent of neuronal WNK kinase activity has an important influence on learning, memory and anxiety-related behaviors, in part, by modulation of neuronal insulin signaling.

Tonic excitation by astrocytic GABA causes neuropathic pain by augmenting neuronal activity and glucose metabolism

Neuropathic pain is a debilitating condition caused by the hyperexcitability of spinal dorsal horn neurons and is often characterized by allodynia. Although neuron-independent mechanisms of hyperexcitability have been investigated, the contribution of astrocyte-neuron interactions remains unclear. Here, we show evidence of reactive astrocytes and their excessive GABA release in the spinal dorsal horn, which paradoxically leads to the tonic excitation of neighboring neurons in a neuropathic pain model. Using multiple electrophysiological methods, we demonstrated that neuronal hyperexcitability is attributed to both increased astrocytic GABA synthesis via monoamine oxidase B (MAOB) and the depolarized reversal potential of GABA-mediated currents (EGABA) via the downregulation of the neuronal K+/Cl− cotransporter KCC2. Furthermore, longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET imaging demonstrated increased regional glucose metabolism in the ipsilateral dorsal horn, reflecting neuronal hyperexcitability. Importantly, inhibiting MAOB restored the entire astrocytic GABA-mediated cascade and abrogated the increased glucose metabolism and mechanical allodynia. Overall, astrocytic GABA-mediated tonic excitation is critical for neuronal hyperexcitability, leading to mechanical allodynia and neuropathic pain.

Frontal and anterior temporal hypometabolism post chemoradiation in head and neck cancer: A real-world PET study.

Adverse neurological effects after cancer therapy are common, but biomarkers to diagnose, monitor, or risk stratify patients are still not validated or used clinically. An accessible imaging method, such as fluorodeoxyglucose positron emission tomography (FDG PET) of the brain, could meet this gap and serve as a biomarker for functional brain changes. We utilized FDG PET to evaluate which brain regions are most susceptible to altered glucose metabolism after chemoradiation in patients with head and neck cancer (HNCa). Real-world FDG PET images were acquired as standard of care before and after chemoradiation for HNCa in 68 patients. Linear mixed-effects voxelwise models assessed changes after chemoradiation in cerebral glucose metabolism quantified with standardized uptake value ratio (SUVR), covarying for follow-up time and patient demographics. Voxelwise analysis revealed two large clusters of decreased glucose metabolism in the medial frontal and polar temporal cortices following chemoradiation, with decreases of approximately 5% SUVR after therapy. These findings provide evidence that standard chemoradiation for HNCa can lead to decreased neuronal glucose metabolism, contributing to literature emphasizing the vulnerability of the frontal and anterior temporal lobes, especially in HNCa, where these areas may be particularly vulnerable to indirect radiation-induced injury. FDG PET shows promise as a sensitive biomarker for assessing these changes.

Drug-drug interactions between propofol and ART drugs: Inhibiting neuronal activity by affecting glucose metabolism.

The use of two or more drugs carries the potential risk of drug-drug interactions (DDIs), which may result in adverse reactions. Some human immunodeficiency virus (HIV)-infected patients who receive antiretroviral therapy (ART) may require general anesthesia with propofol (PRL) before undergoing surgical treatment. Both PRL and ART drugs may lead to neuronal dysfunction, which can be accompanied by energy metabolism disorders. Neurons take in glucose mainly through glucose transporter 3 (Glut3) which is specifically expressed on the cell membranes of neurons. However, to date, no study has examined whether the DDIs of PRL and ART drugs interfere with glucose metabolism and Glut3 expression in neurons. An in vitro model was constructed using the primary cultures of neurons. PRL and ART drugs (EFV, AZT, and 3TC), were added at different concentrations (low, medium, and high). The neurons were exposed to the drugs for 1, 4, 8, and 12 h. The optimal drug concentration and exposure time were selected. The cellular survival rate, glucose concentration, electrophysiology, and the expression of Glut3 were detected. There were no significant changes in the cellular survival rates of the neurons that were exposed to both PRL and ART drugs at low concentrations for 1 h. However, the survival rates of the neurons decreased significantly as the drug concentrations and durations increased. The glucose concentration of the neurons that were exposed to both PRL and the ART drugs was significantly decreased. The glucose concentration of the neurons was not affected by any individual drug. The amplitude of the action potential and the expression of Glut3 were decreased in the neurons that were exposed to both PRL and ART drugs. The main adverse reactions induced by the DDIs between PRL and the ART drugs were decreased glucose metabolism and neuronal damage, which were caused by inhibiting the expression of Glut3. More importantly, we found that decreases in glucose metabolism predated neuronal damage.

Epileptiform Discharges Reduce Neuronal ATP Production by Inhibiting F0F1-ATP Synthase Activity via A Zinc-α2-Glycoprotein-Dependent Mechanism.

Neuronal energy metabolism dysfunction, especially adenosine triphosphate (ATP) supply decrease, is observed in epilepsy and associated with epileptogenesis and prognosis. Zinc-α2-glycoprotein (ZAG) is known as an important modulator of energy metabolism and involved in neuronal glucose metabolism, fatty acid metabolism, and ketogenesis impairment in seizures, but its effect on neuronal ATP synthesis in seizures and the specific mechanism are unclear. In this study, we verified the localization of ZAG in primary cultured neuronal mitochondria by using double-labeling immunofluorescence, immune electron microscopy, and western blot. ZAG level in neuronal mitochondria was modulated by lentiviruses and detected by western blot. The F0F1-ATP synthase activity, ATP level, and acetyl-CoA level were measured. The binding between ZAG and F0F1-ATP synthase was determined by coimmunoprecipitation. We found that both ZAG and F0F1-ATP synthase existed in neuronal mitochondria, and there was mutual binding between them. Epileptiform discharge-induced decrease of mitochondrial ZAG level was reversed by ZAG overexpression. Epileptiform discharge or ZAG knockdown decreased F0F1-ATP synthase activity and ATP level in neurons, which were reversed by ZAG overexpression, while overexpression of ZAG along only increased F0F1-ATP synthase activity but not increased ATP level. Meanwhile, neither epileptiform discharges nor changes of ZAG level can alter the acetyl-CoA level. Moreover, epileptiform discharge did not alter F0F1-ATP synthase level. In conclusion, epileptiform discharge-induced ZAG decrease in neuronal mitochondria is correlated to F0F1-ATP synthase activity inhibition, which may possibly lead to ATP supply impairments. ZAG may be a potential therapeutic target for treating neuronal energy metabolism dysfunction in seizures with further researches.

Lactate as a supplemental fuel for synaptic transmission and neuronal network oscillations: Potentials and limitations.

Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30-70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation-inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5'-triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation.

Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function.

Sleep benefits the restoration of energy metabolism and thereby supports neuronal plasticity and cognitive behaviors. Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes. The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation (CSD). We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex (PrL). We then assessed cerebral functional connectivity (FC) using resting-state functional MRI, neuron/astrocyte metabolism using a metabolic kinetics analysis; dendritic spine densities using sparse-labeling; and miniature excitatory postsynaptic currents (mEPSCs) and action potential (AP) firing rates using whole-cell patch-clamp recordings. In addition, we evaluated cognition via a comprehensive set of behavioral tests. Compared with controls, Sirt6 was significantly decreased (P < 0.05) in the PrL after CSD, accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus, piriform cortex, motor cortex, somatosensory cortex, olfactory tubercle, insular cortex, and cerebellum. Sirt6 overexpression reversed CSD-induced cognitive impairment and reduced FC. Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4 and GABA2 synthesis, which could be fully restored via forced Sirt6 expression. Furthermore, Sirt6 overexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons. These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network, neuronal glucose metabolism, and glutamatergic neurotransmission. Thus, Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.

Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes

The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence and energy metabolism. Energy production and antioxidant defence employ NADH and NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways of glucose metabolism, and both pathways are enhanced by Nrf2 activation. Here, we examined the role of Nrf2 on glucose distribution and the interrelation between NADH production in energy metabolism and NADPH homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout and Keap1-knockdown mice. Employing advanced microscopy imaging of single live cells, including multiphoton fluorescence lifetime imaging microscopy (FLIM) to discriminate between NADH and NADPH, we found that Nrf2 activation increases glucose uptake into neurons and astrocytes. Glucose consumption is prioritized in brain cells for mitochondrial NADH and energy production, with a smaller contribution to NADPH synthesis in the pentose phosphate pathway for redox reactions. As Nrf2 is suppressed during neuronal development, this strategy leaves neurons reliant on astrocytic Nrf2 to maintain redox balance and energy homeostasis.

Diabetes and cognitive function: An evidence-based current perspective.

Several epidemiological studies have clearly identified diabetes mellitus (DM) as a major risk factor for cognitive dysfunction, and it is going to be a major public health issue in the coming years because of the alarming rise in diabetes prevalence across the world. Brain and neural tissues predominantly depend on glucose as energy substrate and hence, any alterations in carbohydrate meta-bolism can directly impact on cerebral functional output including cognition, executive capacity, and memory. DM affects neuronal function and mental capacity in several ways, some of which include hypoperfusion of the brain tissues from cerebrovascular disease, diabetes-related alterations of glucose transporters causing abnormalities in neuronal glucose uptake and metabolism, local hyper- and hypometabolism of brain areas from insulin resistance, and recurrent hypoglycemic episodes inherent to pharmacotherapy of diabetes resulting in neuronal damage. Cognitive decline can further worsen diabetes care as DM is a disease largely self-managed by patients. Therefore, it is crucial to understand the pathobiology of cognitive dysfunction in relation to DM and its management for optimal long-term care plan for patients. A thorough appraisal of normal metabolic characteristics of the brain, how alterations in neural metabolism affects cognition, the diagnostic algorithm for patients with diabetes and dementia, and the management and prognosis of patients when they have this dangerous combination of illnesses is imperative in this context. This evidence-based narrative with the back-up of latest clinical trial reviews elaborates the current understanding on diabetes and cognitive function to empower physicians to manage their patients in day-to-day clinical practice.

Role of nerve signal transduction and neuroimmune crosstalk in mediating the analgesic effects of acupuncture for neuropathic pain.

Neurogenic pain rises because of nervous system damage or dysfunction and is the most difficult to treat among other pathological pains. Acupuncture has been reported as a great treatment option for neurogenic pain owing to its unlimited advantages. However, previous studies on the analgesic effects of acupuncture for NP were scattered and did not form a whole. In this study, we first comprehensively review the relevant basic articles on acupuncture for NP published in the last 5 years and summarize the analgesic mechanisms of acupuncture in terms of nerve signaling, neuro-immune crosstalk, and metabolic and oxidative stress regulation. Acupuncture inhibits the upstream excitatory system and suppresses neuronal transmission efficiency by downregulating glutamate, NMDA receptors, P2XR, SP, CGRP, and other neurotransmitters and receptors in the spinal cord, as well as plasma channels such as TRPV1, HCN. It can also activate the downstream pain inhibitory pathway by upregulating opioid peptide (β-endorphin), MOR receptors, GABA and GABA receptors, bi-directional regulating 5-hydroxytryptamine (5-HT) and its receptors (upregulate 5-HT 1A and downregulate 5-HT7R) and stimulating hypothalamic appetite-modifying neurons. Moreover, neuroinflammation in pain can be inhibited by acupuncture through inhibiting JAK2/STAT3, PI3K/mTOR pathways, down regulating chemokine receptor CX3CR1 on microglia and up regulating adenosine receptor A1Rs on astrocytes, inhibiting the activation of glia and reducing TNF-α and other inflammatory substances. Acupuncture also inhibits neuronal glucose metabolism by downregulating mPFC's GLUT-3 and promotes metabolic alterations of the brain, thus exerting an analgesic effect. In conclusion, the regulation of nerve signal transduction and neuroimmune crosstalk at the peripheral and central levels mediates the analgesic effects of acupuncture for neuropathic pain in an integrated manner. These findings provide a reliable basis for better clinical application of acupuncture in the management of neuropathic pain.

Understanding the Neuronal Requirement for Glycolysis

AbstractBackgroundThe brain has a high energy demand and consumes large amounts of glucose. In Alzheimer’s disease (AD), glucose uptake is reduced, but the significance of this change for neurodegeneration is unclear. Furthermore, whether or not neurons directly take up glucose has been debated in the field. Indeed, the lactate‐shuttle hypothesis predicts that glucose is primarily metabolized by glia or astrocytes into lactate, which is subsequently delivered to neurons and utilized continuously under aerobic conditions. However, studies utilizing glucose analogs challenge that model, and support direct glucose uptake by neurons. Here, we sought to understand the essential role of the neuronal glucose metabolism, to provide a starting point for new approaches to understand and target metabolic changes in AD.MethodTo interrogate the role of neuronal glucose metabolism, we generated mice with targeted deletion of the dominant glucose transporter (GLUT3), or the enzyme that catalyzes the final step in glycolysis (PKM1), specifically in CA1 and other forebrain neurons from postnatal day 19. Mice were assessed with spatial learning and memory behavioral tests, and glucose metabolism and ATP production were monitored in individual neurons and synapses using a FRET‐based live imaging approach.ResultMale and female GLUT3 KO mice showed age‐dependent memory deficits beginning at 7 months of age, and PKM1 KO mice showed impaired memory at 12 months of age, although this defect was only present in female mice. GLUT3KO neurons had decreased basal glucose levels and uptake. GLUT3KO synapses also showed significantly reduced basal ATP levels, and their ATP levels were unresponsive to electrical stimulation, which increases neuronal energy demand. In hippocampal neurons, blocking the last step of glycolysis by PKM1 knockout decreased the basal level of ATP production at synapses in cultures prepared from female pups, and resulted in unresponsiveness to electrical stimulation in both female and male cultures.ConclusionOur results indicate that to function properly and maintain ATP levels at synapses, neurons require glucose that can be taken up directly and metabolized through glycolysis. Therefore, decreased glucose uptake in AD may contribute to neuronal dysfunction and degeneration.

Mechanistic stoichiometric relationship between the rates of neurotransmission and neuronal glucose oxidation: Reevaluation of and alternatives to the pseudo-malate-aspartate shuttle model.

The ~1:1 stoichiometry between the rates of neuronal glucose oxidation (CMRglc-ox-N) and glutamate (Glu)/γ-aminobutyric acid (GABA)-glutamine (Gln) neurotransmitter (NT) cycling between neurons and astrocytes (VNTcycle) has been firmly established. However, the mechanistic basis for this relationship is not fully understood, and this knowledge is critical for the interpretation of metabolic and brain imaging studies in normal and diseased brain. The pseudo-malate-aspartate shuttle (pseudo-MAS) model established the requirement for glycolytic metabolism in cultured glutamatergic neurons to produce NADH that is shuttled into mitochondria to support conversion of extracellular Gln (i.e., astrocyte-derived Gln in vivo) into vesicular neurotransmitter Glu. The evaluation of this model revealed that it could explain half of the 1:1 stoichiometry and it has limitations. Modifications of the pseudo-MAS model were, therefore, devised to address major knowledge gaps, that is, submitochondrial glutaminase location, identities of mitochondrial carriers for Gln and other model components, alternative mechanisms to transaminate α-ketoglutarate to form Glu and shuttle glutamine-derived ammonia while maintaining mass balance. All modified models had a similar 0.5 to 1.0 predicted mechanistic stoichiometry between VNTcycle and the rate of glucose oxidation. Based on studies of brain β-hydroxybutyrate oxidation, about half of CMRglc-ox-N may be linked to glutamatergic neurotransmission and localized in pre-synaptic structures that use pseudo-MAS type mechanisms for Glu-Gln cycling. In contrast, neuronal compartments that do not participate in transmitter cycling may use the MAS to sustain glucose oxidation. The evaluation of subcellular compartmentation of neuronal glucose metabolism in vivo is a critically important topic for future studies to understand glutamatergic and GABAergic neurotransmission.

Alpha-Ketoglutarate Alleviates Neuronal Apoptosis Induced by Central Insulin Resistance through Inhibiting S6K1 Phosphorylation after Subarachnoid Hemorrhage

Neuronal apoptosis after subarachnoid hemorrhage (SAH) is believed to play an important role in early brain injury after SAH. The energy metabolism of neuron is closely related to its survival. The transient hyperglycemia caused by insulin resistance (IR) after SAH seriously affects the prognosis of patients. However, the specific mechanisms of IR after SAH are still not clear. Studies have shown that α-KG takes part in the regulation of IR and cell apoptosis. In this study, we aim to investigate whether α-KG can reduce IR after SAH, improve the disorder of neuronal glucose metabolism, alleviate neuronal apoptosis, and ultimately play a neuroprotective role in SAH-induced EBI. We first measured α-KG levels in the cerebrospinal fluid (CSF) of patients with SAH. Then, we established a SAH model through hemoglobin (Hb) stimulation with HT22 cells for further mechanism research. Furthermore, an in vivo SAH model in mice was established by endovascular perforation. Our results showed that α-KG levels in CSF significantly increased in SAH patients and could be used as a potential prognostic biomarker. In in vitro model of SAH, we found that α-KG not only inhibited IR-induced reduction of glucose uptake in neurons after SAH but also alleviated SAH-induced neuronal apoptosis. Mechanistically, we found that α-KG inhibits neuronal IR by inhibiting S6K1 activation after SAH. Moreover, neuronal apoptosis significantly increased when glucose uptake was reduced. Furthermore, our results demonstrated that α-KG could also alleviate neuronal apoptosis in vivo SAH model. In conclusion, our study suggests that α-KG alleviates apoptosis by inhibiting IR induced by S6K1 activation after SAH.

Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer's Disease.

Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer’s disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against Aβ toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium’s effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1ΔE9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.

Differential role of neuronal glucose and PFKFB3 in memory formation during development.

The consumption of glucose in the brain peaks during late childhood; yet, whether and how glucose metabolism is differentially regulated in the brain during childhood compared to adulthood remains to be understood. In particular, it remains to be determined how glucose metabolism is involved in behavioral activations such as learning. Here we show that, compared to adult, the juvenile rat hippocampus has significantly higher mRNA levels of several glucose metabolism enzymes belonging to all glucose metabolism pathways, as well as higher levels of the monocarboxylate transporters MCT1 and MCT4 and the glucose transporters endothelial-GLUT1 and GLUT3 proteins. Furthermore, relative to adults, long-term episodic memory formation in juvenile animals requires significantly higher rates of aerobic glycolysis and astrocytic-neuronal lactate coupling in the hippocampus. Only juvenile but not adult long-term memory formation recruits GLUT3, neuronal 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and more efficiently engages glucose in the hippocampus. Hence, compared to adult, the juvenile hippocampus distinctively regulates glucose metabolism pathways, and formation of long-term memory in juveniles involves differential neuronal glucose metabolism mechanisms.

Conductor of the Astrocyte-Neuron Metabolic Orchestra

Disorders such as diabetes mellitus, obesity, Parkinson’s, and Alzheimer’s diseases are characterized by central metabolic dysfunctions and pose an enormous economic burden to public health. Annually, several millions of new cases and deaths are reported worldwide, thus substantiating the need to search for new frontiers in combating the growing prevalence and mortality of these diseases. Over the past few years, scientific evidence has consistently shown that the functional sweet taste receptor, T1R2+T1R3 heterodimer, serves to direct (conduct) peripheral glucose metabolism. Recent data have revealed that this heterodimer can also act as a central glucosensor that conducts cerebral glucose metabolism. Emerging reports have confirmed the central role of this receptor as a driver of glucose metabolism in neurons and astrocytes. In this paper, “metabolic orchestra” is used to depict the organizational complexity of the plasma membrane receptor-network involved in coordinating glucose transport and metabolism in the astrocyte-neuron circuitry. In light of recent works, suggesting that the taste receptor is a crucial central glucosensor and master coordinator of glucose metabolism, here, the T1R2+T1R3 heterodimer is referred to as the metabolic conductor of the astrocyte-neuron circuitry, responsible for a highly coordinatedsignaling of glucose molecules and multi-directional cross-talk with other plasma membrane receptors. This concept represents a shift on the astrocyte-neuron metabolic machinery from the GLUT-2 mediated entry of glucose to a more coordinated one, involving multiple players at the plasma membrane. Research focusing on the treatments of brain disorders involving glucose metabolic dysfunctions is also discussed.

Glucose sparing by glycogenolysis (GSG) determines the relationship between brain metabolism and neurotransmission

Over the last two decades, it has been established that glucose metabolic fluxes in neurons and astrocytes are proportional to the rates of the glutamate/GABA-glutamine neurotransmitter cycles in close to 1:1 stoichiometries across a wide range of functional energy demands. However, there is presently no mechanistic explanation for these relationships. We present here a theoretical meta-analysis that tests whether the brain’s unique compartmentation of glycogen metabolism in the astrocyte and the requirement for neuronal glucose homeostasis lead to the observed stoichiometries. We found that blood-brain barrier glucose transport can be limiting during activation and that the energy demand could only be met if glycogenolysis supports neuronal glucose metabolism by replacing the glucose consumed by astrocytes, a mechanism we call Glucose Sparing by Glycogenolysis (GSG). The predictions of the GSG model are in excellent agreement with a wide range of experimental results from rats, mice, tree shrews, and humans, which were previously unexplained. Glycogenolysis and glucose sparing dictate the energy available to support neuronal activity, thus playing a fundamental role in brain function in health and disease.

Biological Functions and Regulatory Mechanisms of Hypoxia-Inducible Factor-1α in Ischemic Stroke.

Ischemic stroke is caused by insufficient cerebrovascular blood and oxygen supply. It is a major contributor to death or disability worldwide and has become a heavy societal and clinical burden. To date, effective treatments for ischemic stroke are limited, and innovative therapeutic methods are urgently needed. Hypoxia inducible factor-1α (HIF-1α) is a sensitive regulator of oxygen homeostasis, and its expression is rapidly induced after hypoxia/ischemia. It plays an extensive role in the pathophysiology of stroke, including neuronal survival, neuroinflammation, angiogenesis, glucose metabolism, and blood brain barrier regulation. In addition, the spatiotemporal expression profile of HIF-1α in the brain shifts with the progression of ischemic stroke; this has led to contradictory findings regarding its function in previous studies. Therefore, unveiling the Janus face of HIF-1α and its target genes in different type of cells and exploring the role of HIF-1α in inflammatory responses after ischemia is of great importance for revealing the pathogenesis and identifying new therapeutic targets for ischemic stroke. Herein, we provide a succinct overview of the current approaches targeting HIF-1α and summarize novel findings concerning HIF-1α regulation in different types of cells within neurovascular units, including neurons, endothelial cells, astrocytes, and microglia, during the different stages of ischemic stroke. The current representative translational approaches focused on neuroprotection by targeting HIF-1α are also discussed.

Glucose metabolic crosstalk and regulation in brain function and diseases.

Brain glucose metabolism, including glycolysis, the pentose phosphate pathway, and glycogen turnover, produces ATP for energetic support and provides the precursors for the synthesis of biological macromolecules. Although glucose metabolism in neurons and astrocytes has been extensively studied, the glucose metabolism of microglia and oligodendrocytes, and their interactions with neurons and astrocytes, remain critical to understand brain function. Brain regions with heterogeneous cell composition and cell-type-specific profiles of glucose metabolism suggest that metabolic networks within the brain are complex. Signal transduction proteins including those in the Wnt, GSK-3β, PI3K-AKT, and AMPK pathways are involved in regulating these networks. Additionally, glycolytic enzymes and metabolites, such as hexokinase 2, acetyl-CoA, and enolase 2, are implicated in the modulation of cellular function, microglial activation, glycation, and acetylation of biomolecules. Given these extensive networks, glucose metabolism dysfunction in the whole brain or specific cell types is strongly associated with neurologic pathology including ischemic brain injury and neurodegenerative disorders. This review characterizes the glucose metabolism networks of the brain based on molecular signaling and cellular and regional interactions, and elucidates glucose metabolism-based mechanisms of neurological diseases and therapeutic approaches that may ameliorate metabolic abnormalities in those diseases.