Generation of Ketone Bodies from Leucine by Cultured Astroglial Cells

Bixel, M. Gabriele; Hamprecht, Bernd

doi:10.1046/j.1471-4159.1995.65062450.x

Cited by 91 publications

(109 citation statements)

References 32 publications

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“…During glucose scarcity, the astrocytes also may contribute to KB formation. Astrocytes in culture have been shown to produce KBs from FAs ( 6 ) and from leucine ( 7 ). The mechanism by which the astrocytes synthesize KBs is very similar to that of cultured hepatocytes.…”

Section: Physiology Of Ketogenesismentioning

confidence: 97%

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

124

108

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This article is available online at http://www.jlr.org family, its importance for purposes of this review is minimal.). KBs have been dubbed "metabolism's ugly duckling" because, in the mid-19th century, they were fi rst discovered in large quantities in the urine of patients succumbing to diabetic ketoacidosis. Thus, it is not surprising that physicians of the era considered KBs to be toxic byproducts of impaired carbohydrate metabolism. It took almost half a century for medical scientists to understand that KBs are normal metabolites manufactured by the liver in increasing amounts when dietary sources of carbohydrate and glucogenic amino acids are in short supply ( 1 ). Unfortunately, some physicians still fail to distinguish between the safe "physiological" hyperketonemia that occurs in healthy individuals during fasting or adherence to a ketogenic diet (KD), and the pathological, out-of-control hyperketonemia associated with insulin-defi cient diabetes.When Owen et al. ( 2 ) reported that during a prolonged fast KBs can provide 60% or more of the brain's daily energy requirement (thereby sparing ‫ف‬ 80 g/day of glucose that otherwise would have been derived largely from breakdown of the body's limited protein stores), it was finally acknowledged that, as in Hans Christian Andersen's 1843 fairy tale, the creature fi rst thought to be an ugly duckling was turning out to be an emerging swan. It became evident that the ketogenic response to starvation is an indispensable metabolic adaptation designed by nature to preserve strength and prolong life during times when food is unavailable ( 3 ) .It is now known that (in nondiabetic individuals), owing to the blood's effi cient buffering capacity, plasma KB Abstract Ketone bodies (KBs ), acetoacetate and ␤ -hydroxybutyrate ( ␤ HB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is diffi cult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to у 2 mM, KB esters, such as 1,3-butanediol monoester of ␤ HB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, ...

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Section: Physiology Of Ketogenesismentioning

confidence: 97%

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

124

108

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“…47,93 Evidence is also given that leucine participates in the transfer of ammonia from neurons to astrocytes. 155,208,209 However, in vivo data supporting these cycles has not yet been shown.…”

Section: Intercellular Ammonia Transfer Complementary To the Glutaminmentioning

confidence: 99%

“…Studies with 15 N-labelled BCAAs indicate that at least one-third of the amino groups of brain glutamate are derived from BCAAs, 217 whereby the nitrogen of leucine may donate at least 25%. BCAAs are oxidized slowly by astrocytes in culture, 209 but are nitrogen donors for the synthesis of glutamate and glutamine in cultured astrocytes. After using the nitrogen from leucine for glutamate-or glutamine synthesis, astrocytes release -KIC to the extracellular fluid.…”

Section: Intercellular Cycling Of Ammonia Through Aspartate Synthesismentioning

confidence: 99%

“…After using the nitrogen from leucine for glutamate-or glutamine synthesis, astrocytes release -KIC to the extracellular fluid. 209 -KIC can be taken up by neurons and converted back to leucine. The cycle is REGULATION OF GLIAL METABOLISM 387 completed after backtransport of leucine to astrocytes.…”

Section: Intercellular Cycling Of Ammonia Through Aspartate Synthesismentioning

confidence: 99%

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Regulation of glial metabolism studied by ¹³C‐NMR

Zwingmann¹,

Leibfritz²

2003

NMR in Biomedicine

106

107

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Glial metabolism and their metabolic trafficking with neurons are essential parts of neuronal function, as they modulate, by this means, neuronal activity. Ex vivo and in vitro 13 C-NMR spectroscopy have been used to monitor neural cellular and tissue metabolism. Special emphasis has been given to the metabolic specialization of astrocytes and its enzymatic regulation. For this purpose primary cell cultures are useful tools to study neuronal-glial metabolic relationships as the extracellular fluid can be investigated and manipulated by various stimuli. In astrocytes, glucose is utilized predominantly anaerobically. Glycolysis is interrelated to the astrocytic TCA cycle via bi-directional signals and metabolic exchange processes between astrocytes and neurons. Besides glucose oxidation, neuronally released glutamate is metabolized through the glial TCA cycle. The flexibility of glutamate metabolism, depending on ammonia and energy homeostasis, and the discovered pyruvate recycling pathway in astrocytes, modulates the glutamine-glutamate cycle. 13 C-NMR studies have extended the concept of the 'non-stoichiometric' glutamate-glutamine cycle between neurons and astrocytes. An alanine-lactate shuttle between neurons and astrocytes contributes to nitrogen transfer from neurons to astrocytes, recycles energy substrates for neurons, and in return promotes intercellular glutamine-glutamate cycling. The conversion of alanine to lactate in astrocytes is regulated by intracytosolic pyruvate compartmentation. In essence, the metabolic flexibility and compartmentalized enzymatic specialization of astrocytes buffers the brain tissue against metabolic impairments and excitotoxicity in response to extracellular stimuli, some of them being released by neurons. These in vitro studies using 13 C-NMR spectroscopy provide important knowledge regarding physiological and pathophysiological regulation of neural metabolism to improve our understanding of general brain function.

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“…Other important energy metabolites released from astrocytes to neurons are ketone bodies, which are derived from fatty acids [51] or leucine [52]. Under particular conditions, such as fasting, uncontrolled diabetes, or maternal milk diet in newborns, ketone bodies are responsible for sustaining the energetic requirements of the brain [32].…”

mentioning

confidence: 99%

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

Mlody

Lorenz

Inak

et al. 2016

Seminars in Cell & Developmental Biology

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The metabolic switch associated with the reprogramming of somatic cells to pluripotency has received increasing attention in recent years. However, the impact of mitochondrial and metabolic modulation on stem cell differentiation into neuronal/glial cells and related brain disease modeling still remains to be fully addressed. Here, we seek to focus on this aspect by first addressing brain energy metabolism and its inter-cellular metabolic compartmentalization. We then review the findings related to the mitochondrial and metabolic reconfiguration occurring upon neuronal/glial specification from pluripotent stem cells (PSCs). Finally, we provide an update of the PSC-based models of mitochondria-related brain disorders and discuss the challenges and opportunities that may exist on the road to develop a new era of brain disease modeling and therapy.3 Mitochondrial remodeling in cell fate specificationThe majority of cellular energy in form of ATP is provided through oxidative phosphorylation (OXPHOS) by mitochondria. Mitochondria are also involved in the metabolism of amino acids, fatty acids, and steroids, and contribute to cell signaling through the modulation of reactive oxygen species (ROS), calcium homeostasis, and apoptosis [1].Furthermore, intermediate metabolites can cross-talk to the nucleus acting as epigenetic regulators [2].In low oxygen environments, a typical conversion process of 1 molecule of glucose results into 2 molecules of ATP through glycolysis in the cytosol, which terminates with the secretion of lactate into the extracellular environment. Under normoxic conditions, the 2 molecules of pyruvate, generated through glycolysis, can enter the mitochondria and undergo further oxidation in the tricarboxylic acid (TCA) cycle, leading to the production of additional 34 molecules of ATP [3]. However, under conditions requiring high proliferative rates, this mitochondrial-based energy generation may be shut-down despite the presence of normal oxygen concentration [4]. This situation, known as aerobic glycolysis or Warburg effect, was first described by Otto Warburg in the context of cancer [5]. Recent studies demonstrated that a Warburg-like effect may also represent a defining feature of stem cells [6][7][8].Since distinct cell types have different energy demands, regulation of mitochondria may represent an essential process allowing the cells to meet their biological requirements.The metabolic identity of cells may in fact be influenced not only by changes in the expression of metabolic genes, but also by modulation of mitochondrial dynamics and mitochondrial DNA (mtDNA) copy number [9,10]. In particular, energy metabolism is shifted towards glycolysis in stem cells, whose mitochondria appear round-shaped with poorlydeveloped cristae [11,12]. This is in sharp contrast to cells with high energy demands, like muscle cells and neurons, where mitochondria are abundant in number and exhibit tubularlike morphology and cristae-rich structures [13]. 4As a consequence, acquisition of a distinct metabot...

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Generation of Ketone Bodies from Leucine by Cultured Astroglial Cells

Cited by 91 publications

References 32 publications

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Regulation of glial metabolism studied by ¹³C‐NMR

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

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Generation of Ketone Bodies from Leucine by Cultured Astroglial Cells

Cited by 91 publications

References 32 publications

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Regulation of glial metabolism studied by 13C‐NMR

Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

Contact Info

Product

Resources

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Regulation of glial metabolism studied by ¹³C‐NMR