Physiological roles of ketone bodies as substrates and signals in mammalian tissues.

Robinson, Alison; Williamson, D.

doi:10.1152/physrev.1980.60.1.143

Cited by 949 publications

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“…Ketone bodies spared glucose oxidation while permitting glycolysis and release of lactate and pyruvate from the brain (Table 9). Glucose-sparing effects of ketone bodies in different organs have been attributed, in part, to increased citrate levels and inhibition by citrate of phosphofructokinase, causing reduced glucose oxidation and release of lactate as gluconeogenic substrate Brain lactate metabolism GA Dienel (Robinson and Williamson, 1980). High levels of ketone bodies (2.5 to 17 mmol/L) and lactate (4 to 8 mmol/L) also reduce glucose oxidation in brain slices and in infused, starved, or fat-fed rats (Table 9).…”

Section: Glucose-sparing Action Of Alternative Substrates That Increamentioning

confidence: 99%

“…The autoradiographic [ 14 C]deoxyglucose method uses a two-compartment Ketone bodies, acetoacetate (AcAc) and b-hydroxybutyrate (BHB) levels in blood increase during prolonged fasting, starvation, and high fat diets. In many tissues including the brain, oxidative metabolism of ketone bodies spares glucose by reducing glucose oxidation, maintaining glycolysis, and releasing lactate, which can be converted back to glucose by gluconeogenesis (Robinson and Williamson, 1980). Although details of the mechanisms of regulation of glucose metabolism when alternative substrates are oxidized are not fully established, elevated ketone body metabolism is associated with an increased concentration of citrate, which, along with other metabolic regulators, is an inhibitor of brain phosphofructokinase within the physiological range (Passonneau and Lowry, 1963).…”

Section: Metabolic Modeling and Simulation Studiesmentioning

confidence: 99%

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Brain Lactate Metabolism: The Discoveries and the Controversies

Dienel

2011

J Cereb Blood Flow Metab

422

434

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Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism involving cellular responses to excitatory neurotransmission are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions. Major conclusions drawn from tabular data summarizing results obtained in many laboratories are as follows: Glutamate-stimulated glycolysis is not an inherent property of all astrocyte cultures. Synaptosomes from the adult brain and many preparations of cultured neurons have high capacities to increase glucose transport, glycolysis, and glucose-supported respiration, and pathway rates are stimulated by glutamate and compounds that enhance metabolic demand. Lactate accumulation in activated tissue is a minor fraction of glucose metabolized and does not reflect pathway fluxes. Brain activation in subjects with low plasma lactate causes outward, brain-toblood lactate gradients, and lactate is quickly released in substantial amounts. Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain. Keywords: astrocyte; brain activation; glucose; lactate shuttling; metabolism; neuron Glucose is the major fuel for the brain, and its metabolism by different pathways has important functions related to energetics, neurotransmission, oxidation-reduction (redox) reactions, and biosynthesis of essential brain components (Figure 1). For many decades, lactate production in the brain was viewed as a consequence of inadequate oxygen delivery, disruption of oxidative metabolism, or mismatch between glycolytic and oxidative rates (Siesjö, 1978), but more recently, the conceptual role of lactate metabolism and function in the normal brain have undergone major changes, shifting from developmental fuel and glycolytic waste product to include its use as a supplemental fuel and signaling molecule. Starting in the 1970s to 1980s studies carried out in different laboratories with diverse experimental interests related to brain function brought attention to upregulation of glycolysis, lactate production, lactate release into the blood, the possibility of lactate shuttling among cell types within the brain, lactate fueling adult brain during exercise, and roles of lactate in the regulation of blood flow; some of these topics are controversial and highly debated. The experimental paradigm and physiologic status of subjects are critical for interpretation of data, and this review first presents a brief historical overview of studies related to brain lactate transport and metabolism, then compares sets of data to provide a perspective and context within which the consistency of simi...

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Section: Glucose-sparing Action Of Alternative Substrates That Increamentioning

confidence: 99%

Section: Metabolic Modeling and Simulation Studiesmentioning

confidence: 99%

Brain Lactate Metabolism: The Discoveries and the Controversies

Dienel

2011

J Cereb Blood Flow Metab

422

434

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“…60 The levels of monocarboxylate transporters decrease after weaning but are known to be elevated in diabetes and in other conditions where insulin resistance occurs, such as prolonged fasting. 61 Mild insulin resistance in E4(Ϫ) subjects may increase the levels of MCT1 transporter proteins and allow for better uptake of KB into the brain. However, this mechanism remains to be tested.…”

Section: Ketosis and Admentioning

confidence: 99%

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

301

120

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Summary: An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, ␤-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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“…These results suggest that ketone bodies are important precursors for synthesis of brain lipids only during the suckling period in which they are indeed among the physiological substrates (Robinson and Williamson, 1980). Using the incorporation of 3H from 3H20 as an index for lipogenic rate, we found that this process is at least 8-fold more active in vivo than in vitro (Table 3).…”

Section: Lipid Synthesis By Developing Rat Brain In Vivo; Cornparisonmentioning

confidence: 79%

“…Ketone bodies are important metabolic substrates for the neonatal rat throughout the suckling period which coincides with the growth spurt of the brain (reviewed in Robinson and Williamson, 1980). Studies with isolated brain preparations demonstrate that ketone bodies can partly replace glucose both as an oxidative and as a lipogenic substrate (Yeh et al, 1977;Patel and Clark, 1980;Patel and Owen, 1977;Lopes-Cardozo et al, 1980).…”

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confidence: 99%

Ketone-body utilization and lipid synthesis by developing rat brain—a comparison between in vivo and in vitro experiments

Lopes‐Cardozo

Klein

1984

Neurochemistry International

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Abstract--The distribution of ketone bodies between oxidation and lipid synthesis was analysed in homogenates of developing rat brain. The capacity for lipid synthesis of homogenized or minced brain preparations was compared with rates of lipid synthesis in vivo, assessed by incorporation of 3H from 3H20 into fatty acids and cholesterol. Brain homogenates of suckling rats (but not those of adults) incorporated label from [3-14C]ketone bodies into lipids, but this process was slow as compared to t4CO2 production (< 5%) and much slower than the total rate of ketone-body utilization (<0.5%). Study of 3H20 incorporation demonstrated that the rates of lipogenesis and cholesterogenesis are at least one order of magnitude higher in vivo than in vitro. Maximal rates of 3H incorporation into fatty acids (3 gmol/g brain, h) and into cholesterol (0.6#mol/g brain, h) were found during the third postnatal week. Adult rats still incorporated 3H into brain fatty acids at an appreciable rate (1/~mol/g brain.h), whereas cholesterogenesis was very low. It is concluded that in vitro measurements of lipid synthesis severely underestimate the rates that occur in developing rat brain in vivo. The high rate of 3H incorporation into lipids by developing and adult rat brain as compared to the amounts of these lipids present in the brain suggests an important contribution of endogenous lipid synthesis during brain development and an appreciable rate of fatty acid turnover during brain growth, but also in the adult brain.

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Physiological roles of ketone bodies as substrates and signals in mammalian tissues.

Cited by 949 publications

References 0 publications

Brain Lactate Metabolism: The Discoveries and the Controversies

Brain Lactate Metabolism: The Discoveries and the Controversies

Ketone Bodies as a Therapeutic for Alzheimer's Disease

Ketone-body utilization and lipid synthesis by developing rat brain—a comparison between in vivo and in vitro experiments

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