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• W2609511098 abstract "Review24 April 2017free access Brain metabolism in health, aging, and neurodegeneration Simonetta Camandola Corresponding Author Simonetta Camandola [email protected] orcid.org/0000-0003-0844-643X Laboratory of Neuroscience, National Institute on Aging, Baltimore, MD, USA Search for more papers by this author Mark P Mattson Corresponding Author Mark P Mattson [email protected] Laboratory of Neuroscience, National Institute on Aging, Baltimore, MD, USA Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Simonetta Camandola Corresponding Author Simonetta Camandola [email protected] orcid.org/0000-0003-0844-643X Laboratory of Neuroscience, National Institute on Aging, Baltimore, MD, USA Search for more papers by this author Mark P Mattson Corresponding Author Mark P Mattson [email protected] Laboratory of Neuroscience, National Institute on Aging, Baltimore, MD, USA Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA Search for more papers by this author Author Information Simonetta Camandola *,1 and Mark P Mattson *,1,2 1Laboratory of Neuroscience, National Institute on Aging, Baltimore, MD, USA 2Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA *Corresponding author. Tel: +1 410 558 8617; E-mail: [email protected] *Corresponding author. Tel: +1 410 558 8463; E-mail: [email protected] The EMBO Journal (2017)36:1474-1492https://doi.org/10.15252/embj.201695810 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the “strengthening” of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress. Introduction The higher cognitive functions of the human brain depend upon the expansion and increased density and complexity of the neocortex during evolution (Rakic, 2009). The enhanced abilities of the human brain to plan complex behaviors, make decisions, and process emotional and social contexts came with hefty energy requirements. Although it is only 2% of the total body weight, the brain accounts for 20% of an individual's energy expenditure at rest (Kety, 1957; Sokoloff, 1960). Among brain cells, neurons expend 70–80% of the total energy, with the remaining portion being utilized by glial cells (astrocytes, oligodendrocytes, and microglia) (Harris et al, 2012; Hyder et al, 2013). Organisms allocate their available energy among the competing needs of maintenance, growth, reproduction, and, particularly in primates, higher cortical functions (communication, imagination, and creativity). A growing body of evidence suggests that metabolic adaptations within the brain and whole body played important roles in the expansion of the cerebral cortex during primate evolution. Several studies comparing the expression of genes and regulatory regions in brains of various primates have shown an up-regulation of genes and metabolites involved in oxidative metabolism and mitochondrial functions in human brains (Grossman et al, 2001, 2004; Cáceres et al, 2003; Uddin et al, 2004; Haygood et al, 2007). Furthermore, recent evidence indicates that an increase in metabolic rate, coupled with a higher predisposition to deposit fat and changes in the allocation of energy supplies, was crucial for the evolution of brain size and complexity (Pontzer et al, 2016). Understanding the metabolic signatures of different brain cells, and their metabolic interactions, will not only advance our understanding of how the brain functions and adapts to environmental demands, but may also elucidate the propensity of the human brain to age-related neurodegenerative disorders. In recent years, it has become evident that metabolic alterations strongly influence the instigation and progression of many neurodegenerative disorders. Decreases in glucose and oxygen metabolic rates of brain cells occur during normal aging (Hoyer, 1982a) and are further exacerbated in disorders such as Alzheimer's (AD), amyotrophic lateral sclerosis (ALS), Parkinson's (PD), and Huntington's (HD) diseases (Hoyer, 1982b). In this review article, we summarize the current knowledge of neural cell energy metabolism in the contexts of normal brain function, adaptive neuroplasticity, and the pathogenesis of neurodegenerative disorders. Brain barriers and metabolite transporters Neurons in the adult brain rely mostly on glucose as an energy source (Kety, 1957; Sokoloff, 1960). However, in some circumstances neurons can use substrates other than glucose. For example, ketone bodies are utilized during brain development and in the adult during prolonged fasting periods (Owen et al, 1967; Nehlig & Pereira de Vasconcelos, 1993), while lactate utilization is increased during intense physical activity (Dalsgaard et al, 2003; van de Hall et al, 2009). Given its high metabolic demands and negligible intrinsic energy stores, the brain depends upon a continuous influx of substrates from the blood. In order to protect the brain from fluctuations in the blood composition that could impact its milieu and functions, the exchanges of molecules between blood and cerebral fluids are regulated by the blood–brain barrier (BBB), and the blood–cerebrospinal fluid barrier (BCSFB). The main function of the these barriers is to limit the free diffusion of solutes between blood and brain fluids, and to selectively transport essential nutrients, ions, and signaling molecules, while removing metabolic waste products. The BBB separates the brain interstitial fluid from the blood and is formed by capillary endothelial cells interconnected by tight and adherens junctions, their underlying basement membrane, pericytes, and the “end feet” of astrocytes (Fig 1). The BBB controls the influx of metabolites such as glucose, amino acids, and ketones from the blood into the brain, while preventing the access of blood-borne molecules and cells (e.g., lymphocytes) that could be detrimental for neuronal functions. The BCSFB is formed by the modified epithelial cells of the choroid plexus which separates the peripheral blood from the CSF, and the arachnoid epithelium separating the cerebral blood from the CSF. In addition to filtering functions similar to the BBB, the epithelial cells of the BCSFB are also responsible for producing the CSF. Figure 1. Nutrient transport across the blood–brain barrierThe blood–brain barrier is formed by capillary endothelial cells surrounded by basement membrane, pericytes, and the astrocyte perivascular end feet. The presence of tight junctions between the endothelial cells strongly inhibits the penetration of water-soluble molecules. Passive diffusion is limited to gases and small nonpolar lipids. All other nutrients require passive or active mediated transporters. GLUT1-5, glucose transporter 1-5; MCT1-4, monocarboxylic acid transporter 1-4. Download figure Download PowerPoint The modalities by which specific molecules cross through the BBB depend upon the nature of the solutes (Fig 1). Passive partition is limited to small nonpolar lipid-soluble molecules, and to diffusible gases such as oxygen and carbon dioxide according to their concentration gradients. The presence of tight junctions restricts paracellular diffusion of polar molecules such as proteins (Zlokovic et al, 1985a,b; Zlokovic & Apuzzo, 1997), which cross the BBB by interacting with receptors or transporters expressed on both the luminal and abluminal membranes, or selectively on one side (Zloković et al, 1987; Zlokovic et al, 1990; Abbott et al, 2010). Large peptides and proteins such as hormones, growth factors, and neuroactive peptides are transferred via receptor-mediated, adsorptive-mediated, and carrier-mediated transport (Zlokovic, 1995, 2008). Based on the requirement or not to hydrolyze ATP to move the solute across the membrane, two major families of transporters have been identified in the BBB: the ATP-binding cassette (ABC) proteins and the solute carrier (SLC) proteins. The ABC transporters include multidrug resistance-associated proteins (MRPs, ABCB1-6), P-glycoprotein, and breast cancer resistance protein (BRPC) (Begley, 2004). These transporters function as efflux pumps that couple ATP hydrolysis to move lipid-soluble molecules against their concentration gradient. The solute carrier proteins comprise a large superfamily of more than 300 members; they are instrumental for ensuring a stable supply of carbohydrates, amino acids, monocarboxylic acids, nucleotides, fatty acids, and organic anions and cations (Abbott et al, 2010). Among the SLC carriers, those that transport hexose and pentose sugars (glucose transporters; GLUTs) and monocarboxylates (monocarboxylic acid transporters; MCTs) are particularly important for brain metabolism. The intake of glucose into the brain is mediated by GLUT1, which is expressed as a 55-kD isoform in endothelial cells of the BBB. A second 45-kD GLUT1 isoform ensures delivery of glucose to glia, ependymal cells, and the choroid plexus. GLUT3 mediates uptake of glucose in neurons; GLUT3 is mainly concentrated in axons and dendrites. GLUT3 has a higher glucose affinity and transport capacity compared to other transporters, and so ensures that neurons receive a constant supply of glucose even when interstitial glucose concentrations are low. Other members of the glucose transporter family are expressed at much lower levels compared to GLUT1 and GLUT3 in specific cell types and/or in specialized brain regions. For example, the insulin-sensitive GLUT4 is present in astrocytes, neurons, and endothelial cells (Kobayashi et al, 1996), and GLUT8 is located in the cytoplasm of neurons mostly in the hippocampus, amygdala, cerebellum, and hypothalamus (Reagan et al, 2001; Ibberson et al, 2002). GLUT2 is expressed in a subset of glutamatergic neurons in the hypothalamus and has recently been identified as a brain glucose sensor that triggers sugar seeking behavior under hypoglycemic conditions (Labouèbe et al, 2016). GLUT6 has been detected in neurons (Doege et al, 2000) and GLUT7 in astrocytes (Maher et al, 1994). In microglia, the most abundant transporter is GLUT5 which has a very low affinity for glucose and mostly fluxes fructose (Mantych et al, 1993). The predominant roles of GLUT1 and GLUT3 in efficiently moving glucose from the blood across the BBB and into neurons have been clearly demonstrated in studies of gene knockout mice. GLUT1+/− mice have a reduced brain size and abnormal motor behavior (Wang et al, 2006), reminiscent of the phenotypes observed in human GLUT1 deficiency syndrome patients (De Vivo et al, 1991). GLUT3+/− mice exhibit abnormal spatial learning and working memory, in addition to perturbed social behavior (Zhao et al, 2010). GLUT8-null homozygous mice have modest reductions of hippocampus volume (Membrez et al, 2006), and locomotion (Schmidt et al, 2008). In addition to facilitative glucose transporters, the endothelial cells of the BBB also express sodium-dependent unidirectional transporters that are members of the solute carrier 5 family (SGLT) 1 and 2. These carriers couple the sodium electrochemical gradient to transfer glucose against its concentration gradient across the membrane. Their role under physiological conditions is not clear, but they appear to be functional during conditions of oxygen/glucose deprivation or ischemia (Yu et al, 2010). Because GLUT1 and GLUT3 transporters are constitutively located on the plasma membrane and do not respond to stimulation with insulin, brain glucose uptake is believed to be insulin-independent. There are 14 MCTs with particular affinities for one or more substrates. MCTs 1–4 are expressed in cells of the BBB (Fig 1) and are responsible for bidirectional passive proton-linked transport of lactate, ketone bodies (i.e., acetoacetate and 3-β-hydroxybutyrate), and pyruvate. MCT1 has high affinity for pyruvate and also transports lactate and ketone bodies; it is present in endothelial cells (Gerhart et al, 1997), astrocytes (Bröer et al, 1997), oligodendrocytes (Lee et al, 2012), and microglia (Moreira et al, 2009). Only a few specific subsets of hypothalamic neurons express MCT1 (Carneiro et al, 2016). MCT2 is the major transporter in neurons (Pierre et al, 2002), and compared to MCT1 has an overall higher affinity for all the substrates (Bröer et al, 1997). MCT2 is concentrated in dendritic spines where it associates with postsynaptic density proteins, as well as the AMPA receptor subunit Glur2 (Bergensen et al, 2005). MCT3 transports lactate and is only expressed in the retinal epithelium and the choroid plexus epithelium (Philp et al, 2001). MCT4 carries lactate and is exclusively expressed in astrocytes (Pellerin et al, 2005). The specific cell distribution patterns and substrate affinities of MCTs in the brain suggest that MCTs play fundamental roles in shuttling energy substrates among different brain cell types. Glucose metabolic pathways in neurons and astrocytes The metabolic fate of glucose in the brain depends upon the cell type and the selective expression of metabolic enzymes. Neurons are predominantly oxidative, while astrocytes are mostly glycolytic (Hiden & Lange, 1962; Hamberger & Hyden, 1963). In addition to the production of adenosine-5′-triphosphate (ATP), glucose is also used to generate metabolic intermediates for the synthesis of fatty acids and other lipids required for membrane and myelin synthesis (Ramsey et al, 1971; Jones et al, 1975); amino acids for protein synthesis and neurotransmitter production (Vrba et al, 1962; Gaitonde & Richter, 1966); and 5-carbon sugars for the synthesis of nucleotides (Gaitonde et al, 1983); and to produce glycogen in astrocytes. In neurons, each molecule of glucose is oxidized via glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation, with the production of carbon dioxide, water, and 30–36 molecules of ATP depending upon the rates of proton leakage in the mitochondria (Fig 2). The glycolytic process metabolizes glucose to pyruvate, which can be actively transported into the mitochondria where it is converted to acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is complexed with citrate which undergoes a series of regenerative enzymatic reactions producing reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) in the TCA cycle. The NADH and FADH2 produced during glycolysis and the TCA cycle are subsequently re-oxidized in the electron transport chain (ETC). ETC. utilizes the energy produced by the transfer of electrons through its various complexes to transport protons across the inner mitochondrial membrane into the intermembrane space. The flux of protons back into the mitochondrial matrix is mediated by the enzyme ATP synthase, which utilizes the energy to generate ATP from ADP. Once inside the cell, glucose is irreversibly converted to glucose-6-phosphate (G6P) by hexokinase (HK). G6P can then be further metabolized via glycolysis or the pentose phosphate pathway (PPP) or can be used for glycogen synthesis. Figure 2. Metabolic pathways of glucose utilization in neurons and astrocytesIn neurons after entering the cell via glucose transporter 3 (GLUT3), glucose is phosphorylated by hexokinase (HK) to glucose-6-phosphate (G6P), which is subsequently routed in the glycolytic pathway and the pentose phosphate pathway (PPP). The end product of glycolysis is pyruvate that enters the mitochondria where it is metabolized through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation in the electron transport chain (ETC.), generating adenosine-5′-triphosphate (ATP) and carbon dioxide (CO2) while consuming oxygen (O2). Pyruvate can also be generated from lactate dehydrogenase 1 (LDH1)-dependent conversion of lactate. In the PPP, G6P is converted to 6-phosphogluconate (6PG) that is transformed in ribulose-5-phosphate (R5P), with the concomitant production of reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is utilized to regenerate oxidized antioxidants such as glutathione (GSH) and thioredoxin. Neurons are not able to store glucose in the form of glycogen due to constitutive degradation of glycogen synthase (GS) via glycogen synthase kinase 3 (GSK3) phosphorylation, and subsequent ubiquitin-dependent proteasomal digestion mediated by the malin–laforin complex. In astrocytes, glucose is imported trough glucose transporter 1 (GLUT1) and preferentially stored as glycogen, or metabolized via glycolysis. The pyruvate generated is converted to lactate thanks to the expression of lactate dehydrogenase 5 (LDH5), and pyruvate dehydrogenase kinase 4 (PDK4)-dependent inhibition of pyruvate dehydrogenase (PDH). The presence of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) allows astrocytes to generate fructose-2,6-bisphosphate (F2,6P) that acts as an allosteric modulator of PKF1 boosting glycolysis. Abbreviations are as follows: F6P, fructose-6-phosphate; PKF1, phosphofructokinase 1; F1,6P, fructose-1,6-diphosphate; G3P, glyceraldehyde-3-phosphate; Mit, mitochondrion; PEP, phosphoenolpyruvate; PKM1, pyruvate kinase M1; PKM2, pyruvate kinase M2; G1P, glucose-1-phosphate; GP, glycogen phosphorylase; APC/C-Cdh1, anaphase-promoting complex C/cytosome-Cdh1; MCT, monocarboxylic acid transporter. Download figure Download PowerPoint Although negligible compared to peripheral energy deposits, glycogen represents the largest energy reserve in the brain. Glycogen metabolism is regulated by two key enzymes, glycogen synthase (GS) and glycogen phosphorylase (GP). The reason why glycogen is produced and stored exclusively in astrocytes (Magistretti et al, 1993) is because in neurons GS is maintained in a constitutively inactive state by hyperphosphorylation via glycogen synthase kinase 3 (GSK3), and subsequent ubiquitin-dependent proteasomal degradation mediated by the malin–laforin complex (Vilchez et al, 2007) (Fig 2 inset). A similar degradation process also occurs for protein targeting to glycogen (PTG), the regulatory subunit of protein phosphatase 1 that is able to activate GS by dephosphorylation, thus preventing the accumulation of glycogen in neurons (Vilchez et al, 2007). The preferred route of G6P metabolism in neurons is the PPP, an anabolic metabolic pathway that converts G6P into 5-carbon sugars utilized for the biosynthesis of nucleotides with generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Based on the cellular requirements, a portion of ribulose-5-phosphate (R5P) can be converted back into the glycolytic intermediates fructose-6-phosphate (F6P) and glyceraldehyde-3-phosphate (G3P). In neurons, this conversion is minimal, and NADPH is utilized as a cofactor for synthesis of fatty acids and myelin, for neurotransmitter turnover, and to maintain redox homeostasis. The maintenance of neuronal antioxidant potential relies on the use of NADPH as cofactor to regenerate reduced glutathione (GSH) (Fig 2) and thioredoxin by glutathione and thioredoxin reductase, respectively. The balance between glycolysis and PPP rates in neurons is very important, and diversion of glucose utilization toward exclusive glycolysis can result in decreased availability of NADPH, increased oxidative stress and cell death (Herrero-Mendez et al, 2009). The preferential use of G6P in the PPP in neurons, as well as their inability to up-regulate glycolysis, is due to the selective expression of enzymes favoring such a metabolic route coupled with the absence of specific glycolysis modulators. In addition to the HK step mentioned above, the glycolytic flux is regulated by phosphofructokinase 1 (PKF1) and pyruvate kinase (PK) (Lowry & Passonneau, 1964). PKF1 catalyzes the phosphorylation of F6P to fructose-1,6-bisphosphate (F1,6P). Its activity is inhibited by metabolites associated with a high energy state (i.e., ATP, citrate) and enhanced by those resulting from high metabolic activity (i.e., ADP, AMP, phosphate), as well as by fructose-2, 6-bisphosphate (F2,6P). It was recently shown that neurons lack the enzyme responsible for the generation of F2,6P, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3) due to continuous ubiquitin-dependent proteasomal degradation (Herrero-Mendez et al, 2009) (Fig 2 inset). While neurons lack Pfkfb3, they express pyruvate kinase M1 (PKM1) (Zhang et al, 2014), a constitutively active enzyme with a very high affinity for phosphoenolpyruvate (PEP), thereby favoring the generation of high levels of pyruvate. This, in association with the expression in neurons of the low-pyruvate-affinity isoform of lactate dehydrogenase (LDH1), prevents pyruvate conversion to lactate and favors its entrance into the TCA cycle (Fig 2). Further metabolic bias toward the TCA cycle results from the lower levels of expression in neurons of pyruvate dehydrogenase kinase 4 (PDK4) which controls the activity of pyruvate dehydrogenase (PDH), and therefore the decarboxylation of pyruvate to acetyl-CoA. Astrocyte utilization of glucose is complementary to that of neurons. A portion of G6P is channeled into glycogen synthesis and PPP, but its predominant metabolism occurs via glycolysis with production of lactate and very low rates of mitochondrial oxidation (Itoh et al, 2003). This metabolic phenotype of astrocytes is the result of their unique expression of various enzymes and transporters. In contrast to neurons, astrocytes express very high levels of Pfkfb3 which favors glycolysis via allosteric activation of PFK by F2,6P (Herrero-Mendez et al, 2009). Furthermore, under basal conditions the levels of PDH phosphorylation are high (Halim et al, 2010) thanks to elevated expression of PDK4 (Zhang et al, 2014), efficiently limiting the conversion of pyruvate to acetyl-CoA (Fig 2). Astrocytes also express low levels of mitochondrial aspartate/glutamate carrier (AGC) decreasing the import of reduced equivalents (NADH) from the cytosol (Ramos et al, 2003). The expression of LDH5, which has a high affinity for pyruvate, rather than LDH1, ensures its conversion to lactate with concomitant oxidation of NADH to NAD+ thus maintaining high rates of NAD+/NADH that further favor aerobic glycolysis. The presence of PKM2 instead of PKM1 also enables astrocytes to easily up-regulate the rate of glycolysis to increase the production of lactate, if needed. Monocarboxylic acid metabolism Over the past few decades, it has become clear that in addition to glucose, neurons can utilize alternate fuels, namely lactate and ketone bodies. Seminal in vitro studies of McIlwain in the 1950s demonstrated that in human cerebral cortex slices, both pyruvate and lactate could replace glucose to support respiration under basal conditions, and during electrical stimulation (McIlwain, 1953). Neurons in vitro have a preference for lactate over glucose when both substrates are provided (Itoh et al, 2003; Bouzier-Sore et al, 2006). However, clear evidence for a role for lactate in brain metabolism in vivo has been obtained only recently. The cell type-specific distribution of MCTs, and the intrinsic metabolic properties of astrocytes and neurons, led to the hypothesis that lactate is shuttled between the two cell types to support neuronal metabolism (Pellerin & Magistretti, 1994) (Fig 2). Such metabolic coupling of astrocytes and neurons is supported by optogenetic studies showing an in vivo lactate gradient from astrocytes to neurons (Mächler et al, 2016). Furthermore, pharmacological inhibition or genetic targeting of MCT2 irreversibly impairs long-term memory in mice (Newman et al, 2011; Suzuki et al, 2011). Long-term memory impairment can be reversed by intrahippocampal administration of lactate, but not glucose, in MCT4-deficient mice (Suzuki et al, 2011). Targeted disruption of MCT1 and MCT2 impairs memory consolidation/reconsolidation in cocaine-induced conditioned place preference and self-administration (Zhang et al, 2016). Heterozygous MCT1 knockout mice have impaired inhibitory avoidance memory (Tadi et al, 2015). Altogether, these results strongly suggest that the neuronal uptake of lactate is important for the establishment of long-term memories. The overall contribution of lactate to brain metabolism varies with its availability. Studies in conscious humans have shown that under resting conditions, lactate uptake by the brain provides about 8% of its energy requirements (van de Hall et al, 2009). The percentage increases up to 20% under conditions of high plasma levels of lactate such as during intense exercise (van de Hall et al, 2009). Furthermore, at various exercise intensities the metabolism of lactate in the brain is higher in trained subjects compared to controls (Kemppainen et al, 2005). This suggests the possibility of adaptive mechanisms allowing the brain to respond to changes in substrate availability. Notably, in rodents acute exercise induces brain region-specific up-regulation of MCTs (Takimoto & Hamada, 2014) and enhances oxidative capacity of cells in the motor cortex (McCloskey et al, 2001). In addition to lactate, brain cells can metabolize the ketone bodies 3-β-hydroxybutyrate (3HB) and acetoacetate (AcAc). Ketones are recognized as an essential energy substrate for the brain during development, delivering up to 30–70% of its energy requirement (Nehlig, 2004); compared to the adult, the immature brain has high activity and levels of MCTs (Gerhart et al, 1997; Pellerin et al, 1998). Also, in rodents the brain activity of enzymes involved in ketone metabolism increases steadily through the suckling period, and then drops after weaning (Page et al, 1971; Middleton, 1973). The high level of ketone utilization during development is necessary to support energy metabolism, as well as the amino acid and lipid biosynthesis required for brain maturation (De Vivo et al, 1975; Yeh et al, 1977). In rats, incorporation of 3HB into amino acids is two- to threefold higher than glucose during the nursing period (De Vivo et al, 1975). Similarly, lipid synthesis, fundamental for myelination, is preferentially sustained by the use of ketones as precursors during the suckling period (Yeh et al, 1977). In addition to anabolic functions, the oxidation of ketones is also important during the early postnatal period (Fig 3). Mice with succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency have normal prenatal development, but right after birth they become ketotic, with reduced plasma levels of glucose and lactate (Cotter et al, 2011). In the adult brain, the utilization of ketones is greatly reduced in the fed state, but can increase considerably under conditions of limited glucose availability as occurs during fasting, starvation, low carbohydrate/high fat intake, and prolonged or intense exercise bouts (Fig 3). Under such conditions, the liver generates ketone bodies from fatty acid and ketogenic amino acid oxidation. Among brain cells, only astrocytes are equipped to generate ketone bodies from fatty acid β-oxidation (Edmond, 1992), but the rates of fatty acid transport are very low compared to those in the liver. All brain cell types are, however, able to uptake ketones, mostly 3HB and AcAc, via MCTs; the ketones are then metabolized to acetyl-CoA to support the cell energy and biosynthetic needs (Fig 3). In adults, the activity of ketone-metabolizing enzymes is high enough that it would easily permit a complete switch from glucose to ketones to support brain energy needs (Krebs et al, 1971). Because ketones are never produced at saturating concentrations, the brain rate of utilization is strictly regulated by their blood concentration (Sokoloff, 1973). Indeed, during ketosis the brain glucose utilization has been shown to decrease by about 10% for each millimole of plasma ketones (LaManna et al, 2009). During medically supervised starvation of obese patients, ketones provide up to 60% of the energy utilized by the brain (Owen et al, 1967). Figure 3. Schematic of ketone body oxidative and anabolic utilization in brainUnder conditions of reduced glucose availability such as low carbohydrates/high-fat diet, exercise, or fasting, the liver utilizes fatty acids mobilized from adipose tissue and ketogenic amino acids (i.e. leucine, lysine, phenylalanine, isoleucine, tryptophan, tyrosine, threonine) to produce acetoacetate (AcAc), 3-β-hydroxybutyrate (3HB), and acetone (Ac). Acetone is considered to have negligible metabolic signi" @default.
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• W2609511098 title "Brain metabolism in health, aging, and neurodegeneration" @default.
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