<b>Introduction:</b> Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. <b>Methods:</b> Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms "glucose transporters" AND "Alzheimer's disease". Human and rodent studies were included while reviews, letters, and <i>in-vitro</i> studies were excluded. <b>Results:</b> Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. <b>Conclusions:</b> GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD.

Brain ischemia is one of the major causes of chronic disability and death worldwide. It is related to insufficient blood supply to cerebral tissue, which induces irreversible or reversible intracellular effects depending on the time and intensity of the ischemic event. Indeed, neuronal function may be restored in some conditions, such as transient ischemic attack (TIA), which may be responsible for protecting against a subsequent lethal ischemic insult. It is well known that the brain requires high levels of oxygen and glucose to ensure cellular metabolism and energy production and that damage caused by oxygen impairment is tightly related to the brain’s low antioxidant capacity. Oxygen is a key player in mitochondrial oxidative phosphorylation (OXPHOS), during which reactive oxygen species (ROS) synthesis can occur as a physiological side-product of the process. Indeed, besides producing adenosine triphosphate (ATP) under normal physiological conditions, mitochondria are the primary source of ROS within the cell. This is because, in 0.2–2% of cases, the escape of electrons from complex I (NADPH-dehydrogenase) and III of the electron transport chain occurring in mitochondria during ATP synthesis leads to the production of the superoxide radical anion (O2•−), which exerts detrimental intracellular effects owing to its high molecular instability. Along with ROS, reactive nitrosative species (RNS) also contribute to the production of free radicals. When the accumulation of ROS and RNS occurs, it can cause membrane lipid peroxidation and DNA damage. Here, we describe the intracellular pathways activated in brain tissue after a lethal/sub lethal ischemic event like stroke or ischemic tolerance, respectively, highlighting the important role played by oxidative stress and mitochondrial dysfunction in the onset of the two different ischemic conditions.

Brain astrocytes are well known for their broad metabolic potential. After glucose deprivation, cultured primary astrocytes maintain a high cellular ATP content for many hours by mobilizing endogenous substrates, but within 24 h the specific cellular ATP content was lowered to around 30% of the initial ATP content. This experimental setting was used to test for the potential of various exogenous substrates to prevent a loss in cellular ATP in glucose deprived astrocytes. The presence of various extracellular monocarboxylates, purine nucleosides or fatty acids prevented the loss of ATP from glucose-deprived astrocytes. Of the 20 proteinogenic amino acids, only alanine, aspartate, glutamate, glutamine, lysine or proline maintained high ATP levels in starved astrocytes. Among these amino acids, proline was found to be the most potent one to prevent the ATP loss. The astrocytic consumption of proline as well as the ability of proline to maintain a high cellular ATP content was prevented in a concentration-dependent manner by the proline dehydrogenase inhibitor tetrahydro-2-furoic acid. Analysis of the concentration-dependencies obtained by considering the different carbon content of the applied substrates revealed that fatty acids and proline are more potent than glucose and monocarboxylates as exogenous substrates to prevent ATP depletion in glucose-deprived astrocytes. These data demonstrate that cultured astrocytes can utilise a wide range of extracellular substrates as fuels to support mitochondrial ATP regeneration and identify proline as potent exogenous substrate for the energy metabolism of starved astrocytes.

Glucose is the primary energy source for neural stem cells (NSCs), supporting their proliferation, differentiation, and quiescence. However, the high demand for glucose during brain development often exceeds its supply, leading to the utilization of alternative energy sources including ketone bodies. Ketone bodies, including β‐hydroxybutyrate, are short‐chain fatty acids produced through hepatic ketogenesis and play a crucial role in providing energy and the biosynthetic components for NSCs when required. The interplay between glucose and ketone metabolism influences NSC behavior and fate decisions, and disruptions in these metabolic pathways have been linked to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Additionally, ketone bodies exert neuroprotective effects on NSCs and modulate cellular responses to oxidative stress, energy maintenance, deacetylation, and inflammation. As such, understanding the interdependence of glucose and ketone metabolism in NSCs is crucial to understanding their roles in NSC function and their implications for neurological conditions. This article reviews the mechanisms of glucose and ketone utilization in NSCs, their impact on NSC function, and the therapeutic potential of targeting these metabolic pathways in neurological disorders.

The brain’s high demand for energy necessitates tightly regulated metabolic pathways to sustain physiological activity. Glucose, the primary energy substrate, undergoes complex metabolic transformations, with mitochondria playing a central role in ATP production via oxidative phosphorylation. Dysregulation of this metabolic interplay is implicated in Alzheimer’s disease (AD), where compromised glucose metabolism, oxidative stress, and mitochondrial dysfunction contribute to disease progression. This review explores the intricate bioenergetic crosstalk between astrocytes and neurons, highlighting the function of mitochondrial uncoupling proteins (UCPs), particularly UCP4, as important regulators of brain metabolism and neuronal function. Predominantly expressed in the brain, UCP4 reduces the membrane potential in the inner mitochondrial membrane, thereby potentially decreasing the generation of reactive oxygen species. Furthermore, UCP4 mitigates mitochondrial calcium overload and sustains cellular ATP levels through a metabolic shift from mitochondrial respiration to glycolysis. Interestingly, the levels of the neuronal UCPs, UCP2, 4 and 5 are significantly reduced in AD brain tissue and a specific UCP4 variant has been associated to an increased risk of developing AD. Few studies modulating the expression of UCP4 in astrocytes or neurons have highlighted protective effects against neurodegeneration and aging, suggesting that pharmacological strategies aimed at activating UCPs, such as protonophoric uncouplers, hold promise for therapeutic interventions in AD and other neurodegenerative diseases. Despite significant advances, our understanding of UCPs in brain metabolism remains in its early stages, emphasizing the need for further research to unravel their biological functions in the brain and their therapeutic potential.

A high cellular concentration of adenosine triphosphate (ATP) is essential to fuel many important functions of brain astrocytes. Although cellular ATP depletion has frequently been reported for astrocytes, little is known on the metabolic pathways that contribute to ATP restoration by ATP-depleted astrocytes. Incubation of cultured primary rat astrocytes in glucose-free buffer for 60 min with the mitochondrial uncoupler BAM15 lowered the cellular ATP content by around 70%, the total amount of adenosine phosphates by around 50% and the adenylate energy charge (AEC) from 0.9 to 0.6. Testing for ATP restoration after removal of the uncoupler revealed that the presence of glucose as exclusive substrate allowed the cells to restore within 6 h around 80% of the initial ATP content, while coapplication of adenosine plus glucose enabled the cells to fully restore their initial ATP content within 60 min. A rapid but incomplete and transient ATP restoration was found for astrocytes that had been exposed to adenosine alone. This restoration was completely prevented by application of the pyruvate uptake inhibitor UK5099, the respiratory chain inhibitor antimycin A or by the continuous presence of BAM15. However, the presence of these compounds strongly accelerated the release of lactate from the cells, suggesting that the ribose moiety of adenosine can serve as substrate to fuel some ATP restoration via mitochondrial metabolism. Finally, the adenosine-accelerated ATP restoration in glucose-fed astrocytes was inhibited by the presence of the adenosine kinase inhibitor ABT-702. These data demonstrate that astrocytes require for a rapid and complete ATP restoration the presence of both glucose as substrate and adenosine as AMP precursor.

The brain is an energy demanding organ, constituting about 20 % of the body's resting metabolic rate. An efficient energy metabolism is critical to neuronal functions. Glucose serves as the primary essential energy source for the adult brain and plays a critical role in supporting neural growth and development. Endocrine disrupting chemicals (EDCs) such as phthalates has been shown to have a negative impact on neurological functions. The impact of diisononyl phthalate (DiNP) on neural energy transduction using cellular energy metabolizing enzymes as indicators was examined. Over the course of 14 days, eighteen (18) albino rats divided into three groups (1,2 and 3) of six albino rats were given Tween-80/saline, 20 and 200 mg/kg body weight respectively. In the brain, we assessed histological changes as well as activities of selected enzymes of energy metabolism such as the glycolytic pathway, citric acid cycle and mitochondrial electron transport-linked complexes. Activities of the glycolytic and TCA cycle enzymes assayed were significantly decreased except citrate synthase activity with no statistically significant change following the administration of DiNP. Also, respiratory chain complexes (Complex I-IV) activities were significantly reduced when compared to control. DiNP exposure altered the histological integrity of various brain sections. These include degenerated Purkinje neurons, distortion of the granular layer and Purkinje cell layer. Data from this study indicated impaired brain energy metabolism via down-regulation of enzymes of cellular respiration of the glycolytic and oxidative phosphorylation pathways and altered brain histoarchitecture orchestrated by DiNP exposure.

Abstract Background/Objective: Brain glucose metabolism, as measured by 18 F-FDG PET/CT, reflects regional brain function and activity. Substance addiction has been shown to disrupt this metabolic activity, even though the affected brain regions and extent of disruption vary by substance and stage of addiction. This systematic review and meta-analysis aimed to evaluate the effects of substance use and dependence on cerebral glucose metabolism rate (CMR Glu ) measured by 18 F-FDG PET/CT imaging, regardless of study design or subject conditions. Materials and Methods : A systematic search was conducted following PRISMA guidelines to identify eligible human studies that used 18 F-FDG PET in individuals with substance dependence. Meta-analysis was performed using a random-effects model, reporting Hedges’ g with 95% confidence intervals (CIs). Results : Out of 385 records, ten studies met the inclusion criteria, covering substances such as nicotine, morphine, ethanol, methamphetamine, cocaine, and marijuana, and seven were eligible for meta-analysis. Addiction was consistently associated with hypometabolism in the prefrontal cortex, anterior cingulate cortex, and thalamus, which are areas involved in reward, cognition and emotion regulation. Meta-analysis revealed a significant reduction in CMR Glu overall ( g = 0.92; 95% CI: − 1.27 to -0.57). Heterogeneity was moderate to high (I 2 = 70.43%, p = 0.002). Conclusion : Addiction leads to glucose hypometabolism in brain regions across different stages, whether during active use, withdrawal, or prolonged abstinence, regardless of the substance involved. 18 F-FDG PET serves as a valuable molecular imaging tool to detect these brain changes and has great potential for monitoring recovery progress, understanding the withdrawal process, and evaluating treatment response. Clinical trial number: Not Applicable

ONE ■ FUEL METABOLISM 1. BRAIN AND OTHER NEURAL TISSUES The brain and other neural tissues … triacylglycerol. • The brain and red blood cells utilize glucose as their primary energy source under … Insulin stimulates the transport of glucose into the brain. (C) Liver and skeletal muscle

body glucose utilization. The brain mostly uses glucose for energy, and deprivation of glucose, as can happen in hypoglycemia, can result in loss of consciousness The human brain is the central organ of the nervous system, and with the spinal cord, comprises the central nervous system. It consists of the cerebrum, the brainstem and the cerebellum. The brain controls most of the activities of the body, processing, integrating, and coordinating the information it receives from the sensory nervous system. The brain integrates sensory information and coordinate Th…

ABSTRACT Purpose COVID-19, caused by the SARS-CoV-2 virus, has significantly altered modern society and lifestyles. We investigated its impact on brain glucose metabolism by meta-analyzing existing studies that utilized 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans of the brain. Methods We conducted a systematic search of MEDLINE and EMBASE databases from inception to August 2023 for English-language publications using the keywords “positron emission tomography,” “single-photon emission computed tomography,” and “COVID-19.” We included original research articles that reported changes in brain glucose metabolism following COVID-19 infection. ALE values from these studies were aggregated and tested against a null hypothesis that anticipated a random distribution of ALE values, which proved to be significantly higher than chance. Results We identified eight papers that met our inclusion criteria. Significant increases in brain glucose metabolism were noted in the left anterior cingulate gyrus, right thalamus, and brainstem. In children with COVID-19, decreased glucose metabolism was observed in the right and left cerebellum, left amygdala/hippocampus, left anterior cingulate gyrus, and right amygdala. In adults with COVID-19, decreased metabolism was seen in the right temporal lobe, brainstem (acute phase), left posterior cingulate gyrus, left precuneus, right cerebellum, right insula, right anterior cingulate gyrus, left occipital lobe, and left globus pallidus (chronic phase). Conclusion COVID-19 impacts brain glucose metabolism, typically manifesting as areas of decreased metabolism in 18 F-FDG PET scans, though increases are also observed. These changes in metabolism vary with the patient’s age and the time elapsed between the diagnosis of COVID-19 and the PET scan.

The use ofmodern neuroimaging approaches has demonstrated resting-state regional cerebralblood flow (rCBF) to be tightly coupled to resting cerebral glucose metabolism(rCMRglu) in healthy brains. In schizophrenia, several lines of evidence point towardsaberrant neurovascular coupling, especially in the prefrontal regions. To investigatethis, we used Signed Differential Mapping to undertake a voxel-based bimodal metaanalysisexamining the relationship between rCBF and rCMRglu in schizophrenia, asmeasured by Arterial Spin Labeling (ASL) and 18Flurodeoxyglucose Positron EmissionTomography (FDG-PET) respectively. We used 19 studies comprised of data from 557patients and 584 controls. Our results suggest that several key regions implicated in thepathophysiology of schizophrenia such as the frontoinsular cortex, dorsal ACC,putamen, and temporal pole show conjoint metabolic and perfusion abnormalities inpatients. In contrast, discordance between metabolism and perfusion were seen insuperior frontal gyrus and cerebellum, indicating that factors contributing toneurovascular uncoupling (e.g. inflammation, mitochondrial dysfunction, oxidativestress) are likely operates at these loci. Hybrid ASL-PET studies focusing on theseregions could confirm our proposition.

In a cell, the fluxes of matter and energy are highly controlled so that cells can maintain their organization and multiply when needed. We have discussed in the previous chapter that consecutive reactions can be driven through coupling favorable reactions to unfavorable reactions, many of those benefiting from the ΔGo of ATP hydrolysis. Synthesizing ATP involves using energy associated to the chemical processing of nutrients or dedicated molecules stored for this purpose (catabolic metabolism). When in excess, the nutrients tend to engage series of reactions whose end products are the storage molecules (anabolic metabolism) for later use. This shift implies a complex network of metabolisms that have to be inhibited or activated. Inhibition and activation occur selectively at specific reactions which in turn occur in specific locations and precise timings inside cells. In addition, it requires that different cells in the same tissue or in different tissues operate coordinately. Liver, adipose tissue, muscle, and brain, for instance, need to be coordinated so that when the brain and muscle need specific nutrients to operate, this process does not conflict with processes in other organs and no failure of the body function as a whole occurs.

(the cytosol). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine Glycolysis is the metabolic pathway that converts glucose (C6H12O6) into pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes. The wide occu Pyruvate + NADH + H+ → Lactate + NAD+ This process occurs in the bacteria involved in making yogurt (the lactic acid causes the milk to curdle). This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time. Some organisms, such as yeast, convert NADH back to NAD+ in a process called ethanol fermentation. In this process, the pyruvate is converted first to acetaldehyde and carbon dioxide, and then to ethanol. Lactic acid fermentation and ethanol fermentation can occur in the absence of oxygen. This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source. Anoxic regeneration of NAD+ is only an effective means of energy production during short, intense exercise in vertebrates, for a period ranging from 10 seconds to 2 minutes during a maximal effort in humans. (At lower exercise intensities it can sustain muscle activity in diving animals, such as seals, whales and other aquatic vertebrates, for very much longer periods of time.) Under these conditions NAD+ is replenished by NADH donating its electrons to pyruvate to form lactate. This produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules in bacteria). But the speed at which ATP is produced in this manner is about 100 times that of oxidative phosphorylation. The pH in the cytoplasm quickly drops when hydrogen ions accumulate in the muscle, eventually inhibiting the enzymes involved in glycolysis. The burning sensation in muscles during hard exercise can be attributed to the release of hydrogen ions during the shift to glucose fermentation from glucose oxidation to carbon dioxide and water, when aerobic metabolism can no longer keep pace with the energy demands of the muscles. These hydrogen ions form a part of lactic acid. The body falls back on this less efficient but faster method of producing ATP under low oxygen conditions. This is thought to have been the primary means…