scholarly journals Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport

Metabolites ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 889
Author(s):  
Tatsuya Iso ◽  
Masahiko Kurabayashi
Keyword(s):  
Alternative Fuels ◽  
Molecular Mechanisms ◽  
Ketone Bodies ◽  
Contractile Function ◽  
Tca Cycle ◽  
Cardiac Metabolism ◽  
Capillary Endothelium ◽  
Fatty Acid Transport ◽  
Contractile Dysfunction

The heart is a metabolic omnivore that combusts a considerable amount of energy substrates, mainly long-chain fatty acids (FAs) and others such as glucose, lactate, ketone bodies, and amino acids. There is emerging evidence that muscle-type continuous capillaries comprise the rate-limiting barrier that regulates FA uptake into cardiomyocytes. The transport of FAs across the capillary endothelium is composed of three major steps—the lipolysis of triglyceride on the luminal side of the endothelium, FA uptake by the plasma membrane, and intracellular FA transport by cytosolic proteins. In the heart, impaired trans-endothelial FA (TEFA) transport causes reduced FA uptake, with a compensatory increase in glucose use. In most cases, mice with reduced FA uptake exhibit preserved cardiac function under unstressed conditions. When the workload is increased, however, the total energy supply relative to its demand (estimated with pool size in the tricarboxylic acid (TCA) cycle) is significantly diminished, resulting in contractile dysfunction. The supplementation of alternative fuels, such as medium-chain FAs and ketone bodies, at least partially restores contractile dysfunction, indicating that energy insufficiency due to reduced FA supply is the predominant cause of cardiac dysfunction. Based on recent in vivo findings, this review provides the following information related to TEFA transport: (1) the mechanisms of FA uptake by the heart, including TEFA transport; (2) the molecular mechanisms underlying the induction of genes associated with TEFA transport; (3) in vivo cardiac metabolism and contractile function in mice with reduced TEFA transport under unstressed conditions; and (4) in vivo contractile dysfunction in mice with reduced TEFA transport under diseased conditions, including an increased afterload and streptozotocin-induced diabetes.

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Perike Srikanth ◽  
Andrielle E Capote ◽  
Alsina Katherina M ◽  
Benjamin Levin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Francisco J Gonzalez-Gonzalez ◽  
Srikanth Perike ◽  
Frederick Damen ◽  
Andrielle Capote ◽  
Katherina M Alsina ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Right Atrial ◽  
Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

scholarly journals Stable Isotopes for Tracing Cardiac Metabolism in Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Anja Karlstaedt
Keyword(s):  
Cardiovascular Disease ◽  
Stable Isotope ◽  
Isotope Labeling ◽  
Contractile Function ◽  
Ex Vivo ◽  
Cardiac Metabolism ◽  
Metabolic Adaptation ◽  
Cardiovascular Research ◽  
Metabolic Remodeling

Although metabolic remodeling during cardiovascular diseases has been well-recognized for decades, the recent development of analytical platforms and mathematical tools has driven the emergence of assessing cardiac metabolism using tracers. Metabolism is a critical component of cellular functions and adaptation to stress. The pathogenesis of cardiovascular disease involves metabolic adaptation to maintain cardiac contractile function even in advanced disease stages. Stable-isotope tracer measurements are a powerful tool for measuring flux distributions at the whole organism level and assessing metabolic changes at a systems level in vivo. The goal of this review is to summarize techniques and concepts for in vivo or ex vivo stable isotope labeling in cardiovascular research, to highlight mathematical concepts and their limitations, to describe analytical methods at the tissue and single-cell level, and to discuss opportunities to leverage metabolic models to address important mechanistic questions relevant to all patients with cardiovascular disease.

Abstract 13725: Limited Fatty Acid Use by CD36 Deficiency Accelerates the Development of Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ryo Kawakami ◽  
Yogi Umbarawan ◽  
Tatsuya Iso ◽  
Norimichi Koitabashi ◽  
Hiroaki Sunaga ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Diabetic Cardiomyopathy ◽  
Energy Demand ◽  
Tca Cycle ◽  
Contractile Dysfunction ◽  
Transmembrane Glycoprotein ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction ◽  
Systolic And Diastolic Function

Diabetes is an independent risk factor for the development of heart failure. In diabetic hearts, it has been reported that increased fatty acid (FA) uptake and deranged FA use result in accumulation of cardiotoxic lipids and reduced cardiac efficiency that compromise systolic and diastolic function. To date, lipotoxicity hypothesis is prevailing as a key event driving diabetic cardiomyopathy and it is proposed that limited FA use is beneficial for diabetic hearts. However, it has not been fully studied whether limited FA use is actually beneficial in-vivo beating hearts in diabetes. CD36, a transmembrane glycoprotein, has a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport and oxidation with marked enhancement of glucose use. In this study, we explored whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. Contrary to our expectations, we found that cardiac contractile dysfunction was deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake, estimated by 18 F-FDG uptake, was not reduced in CD36KO-STZ hearts, total energy supply, estimated by the pool size of the TCA cycle, was significantly reduced in CD36KO-STZ hearts. Isotopomer analysis with 13 C 6 -glucose revealed that accelerated glycolysis, estimated by enrichment of 13 C 3 -lactate, 13 C 2 -alanine, 13 C 2 -citrate and 13 C 2 -malate, in CD36KO hearts was markedly suppressed by STZ treatment. On the other hand, levels of ceramides, cardiotoxic lipids from excessive FA, were not elevated in CD36KO-STZ hearts compared to WT-STZ. Further, increased energy demand induced by transverse aortic constriction resulted in synergistic exacerbation of cardiac contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis, leading to cardiac contractile dysfunction. Therefore, it is very likely that enhanced FA use in diabetic hearts occurs to compensate for reduced glucose use, and that limitation of FA utilization could be detrimental to the development of diabetic cardiomyopathy.

scholarly journals Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion

2011 ◽  
Vol 300 (2) ◽  
pp. H702-H711 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Chun-An Chen ◽  
Lin Xie ◽  
...  
Keyword(s):  
Heart Rate ◽  
Thyroid Hormone ◽  
Myocardial Ischemia ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Metabolism ◽  
Mouse Heart ◽  
Myocardial Ischemia Reperfusion

There is emerging evidence that treatment with thyroid hormone (TH) can improve postischemic cardiac function. 3,5-Diiodothyropropionic acid (DITPA), a TH analog, has been proposed to be a safer therapeutic agent than TH because of its negligible effects on cardiac metabolism and heart rate. However, conflicting results have been reported for the cardiac effects of DITPA. Importantly, recent clinical trials demonstrated no symptomatic benefit in patients with DITPA despite some improved hemodynamic and metabolic parameters. To address these issues, dose-dependent effects of DITPA were investigated in mice for baseline cardiovascular effects and postischemic myocardial function and/or salvage. Mice were treated with subcutaneous DITPA at 0.937, 1.875, 3.75, or 7.5 mg·kg−1·day−1 for 7 days, and the results were compared with untreated mice for ex vivo and/or in vivo myocardial ischemia-reperfusion (I/R). DITPA had no effects on baseline body temperature, body weight, or heart rate; however, it mildly increased blood pressure. In isolated hearts, baseline contractile function was significantly impaired in DITPA-pretreated mice; however, postischemic recovery was comparable between untreated and DITPA-treated groups. In vivo baseline cardiac parameters were significantly affected by DITPA, with increased ventricular dimensions and decreased contractile function. Importantly, DITPA-treated mice demonstrated high prevalence of fatal cardiac rhythm abnormalities during in vivo ischemia and/or reperfusion. There were no improvements in myocardial infarction and postischemic fractional shortening with DITPA. Myocardial sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and heat shock protein (HSP) levels remained unchanged with DITPA treatment. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R.

A direct test of the hypothesis that increased microtubule network density contributes to contractile dysfunction of the hypertrophied heart

2008 ◽  
Vol 294 (5) ◽  
pp. H2231-H2241 ◽  
Author(s):  
Guangmao Cheng ◽  
Michael R. Zile ◽  
Masaru Takahashi ◽  
Catalin F. Baicu ◽  
D. Dirk Bonnema ◽  
...  
Keyword(s):  
Contractile Function ◽  
Pressure Overload ◽  
Network Density ◽  
Contractile Dysfunction ◽  
Microtubule Network ◽  
Microtubule Stability ◽  
Hypertrophied Myocardium ◽  
Direct Support

Contractile dysfunction in pressure overload-hypertrophied myocardium has been attributed in part to the increased density of a stabilized cardiocyte microtubule network. The present study, the first to employ wild-type and mutant tubulin transgenes in a living animal, directly addresses this microtubule hypothesis by defining the contractile mechanics of the normal and hypertrophied left ventricle (LV) and its constituent cardiocytes from transgenic mice having cardiac-restricted replacement of native β4-tubulin with β1-tubulin mutants that had been selected for their effects on microtubule stability and thus microtubule network density. In each case, the replacement of cardiac β4-tubulin with mutant hemagglutinin-tagged β1-tubulin was well tolerated in vivo. When LVs in intact mice and cardiocytes from these same LVs were examined in terms of contractile mechanics, baseline function was reduced in mice with genetically hyperstabilized microtubules, and hypertrophy-related contractile dysfunction was exacerbated. However, in mice with genetically hypostabilized cardiac microtubules, hypertrophy-related contractile dysfunction was ameliorated. Thus, in direct support of the microtubule hypothesis, we show here that cardiocyte microtubule network density, as an isolated variable, is inversely related to contractile function in vivo and in vitro, and microtubule instability rescues most of the contractile dysfunction seen in pressure overload-hypertrophied myocardium.

scholarly journals POS0400 METABOLIC CHANGES INDUCED BY ANTI-MALONDIALDEHYDE/MALINDIALDEHYDE-ACETALDEHYDE ANTIBODIES PROMOTE OSTEOCLAST DEVELOPMENT

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 429-429
Author(s):  
K. Sakuraba ◽  
A. Krishnamurthy ◽  
A. Circiumaru ◽  
V. Joshua ◽  
H. Wähämaa ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Bone Loss ◽  
Molecular Mechanisms ◽  
Cellular Metabolism ◽  
Tca Cycle ◽  
Tartrate Resistant Acid Phosphatase ◽  
Fcγ Receptor ◽  
Research Support

Background:Malondialdehyde (MDA) is a highly reactive compound generated during lipid-peroxidation in conditions associated with oxidative stress. MDA can irreversibly modify proteins (e.g. lysine, arginine and histidine residues). In addition, acetaldehyde can further react with MDA adducts to form malondialdehyde-acetaldehyde (MAA) modification. Such protein modifications can lead to immunogenic neo-epitopes that are recognized by autoantibodies. In fact, anti-MDA/MAA IgG antibodies are significantly increased in the serum of patients with autoimmune diseases, such as rheumatoid arthritis (RA) (1). Interestingly, anti-MDA/MAA antibodies have been shown to promote osteoclast (OC) differentiation in vitro suggesting a potential role for these autoantibodies in bone damage associated with RA (1).Objectives:Little is known about the molecular mechanisms activated by autoantibodies in RA. Here, we elucidate the pathways specifically triggered by anti-MDA/MAA autoantibodies in developing osteoclasts.Methods:Recombinant human monoclonal anti-MDA/MAA antibodies, which were previously cloned from single synovial B cells of RA patients, were added to different OC assays. OCs were generated from monocyte-derived macrophages in the presence of the cytokines RANK-L and M-CSF. OC development was monitored by light microscopy following tartrate-resistant acid phosphatase staining and by erosion assays using calcium phosphate-coated plates. Bone morphometrics were studied in anti-MDA/MAA-injected mice using X-ray microscopy. Cellular metabolism was analyzed by mass spectrometry, Seahorse XF Analyzer and a colorimetric L-Lactate assay.Results:Anti-MDA/MAA antibodies induced a robust OC differentiation in vitro and bone loss in vivo. The anti-MDA/MAA antibodies acted on developing OCs by increasing glycolysis via an Fcγ receptor I-mediated pathway and the upregulation of the transcription factors HIF-1α, Myc and CHREBP. Such regulation of cellular metabolism was exclusively observed in the presence of the osteoclastogenic anti-MDA/MAA clones, whereas other RA-associated autoantibodies (anti-MDA/MAA or anti-citrullinated protein antibodies) had no effect on metabolism. The anti-MDA/MAA treatment induced a shift in the tricarboxylic acid (TCA) cycle activity in developing OCs, leading to the accumulation of citrate and aconitate.Conclusion:We described a novel type of autoantibody-induced pathway in RA, which might contribute to increased OC activation and a consequent bone loss. Anti-MDA/MAA antibodies promoted osteoclast development by increasing glycolysis and by modulating the TCA cycle through a signaling pathway that included Fcγ receptor I and a network of transcription factors acting on glycolysis. A TCA cycle bias towards citrate production suggests that the anti-MDA/MAA antibodies might stimulate OCs via increasing lipid biosynthesis in the cells.References:[1]Grönwall C. et al. J. Autoimmunity 84 (2017): 29-45.Acknowledgements:This Project has received funding from FOREUM, Foundation for Research in Rheumatology, from the European Research Council (ERC) grant agreement CoG 2017 - 7722209_PREVENT RA, the EU/EFPIA Innovative Medicine Initiative grant agreement 777357_RTCure, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse and Knut and Alice Wallenberg Foundation.Disclosure of Interests:Koji Sakuraba: None declared, Akilan Krishnamurthy: None declared, Alexandra Circiumaru: None declared, Vijay Joshua: None declared, Heidi Wähämaa: None declared, Marianne Engström: None declared, Meng Sun: None declared, Xiaowei Zheng: None declared, Cheng Xu: None declared, Khaled Amara: None declared, Vivianne Malmström Grant/research support from: collaboration with Pfizer, unrelated to the abstract, Sergiu-Bogdan Catrina: None declared, Caroline Grönwall: None declared, Bence Réthi: None declared, Anca Catrina Grant/research support from: collaboration with BMS and Pfizer, unrelated to the present abstract

scholarly journals Rapid metabolic and bioenergetic adaptations of astrocytes under hyperammonemia – a novel perspective on hepatic encephalopathy

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Marcel Zimmermann ◽  
Andreas S. Reichert
Keyword(s):  
Hepatic Encephalopathy ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Therapeutic Strategies ◽  
Cellular Processes ◽  
Cellular Models ◽  
The Tca Cycle ◽  
Underlying Mechanisms

Abstract Hepatic encephalopathy (HE) is a well-studied, neurological syndrome caused by liver dysfunctions. Ammonia, the major toxin during HE pathogenesis, impairs many cellular processes within astrocytes. Yet, the molecular mechanisms causing HE are not fully understood. Here we will recapitulate possible underlying mechanisms with a clear focus on studies revealing a link between altered energy metabolism and HE in cellular models and in vivo. The role of the mitochondrial glutamate dehydrogenase and its role in metabolic rewiring of the TCA cycle will be discussed. We propose an updated model of ammonia-induced toxicity that may also be exploited for therapeutic strategies in the future.

Echocardiographic assessment of cardiac function in diabeticdb/db and transgenic db/db-hGLUT4 mice

2002 ◽  
Vol 283 (3) ◽  
pp. H976-H982 ◽  
Author(s):  
Lisa M. Semeniuk ◽  
Albert J. Kryski ◽  
David L. Severson
Keyword(s):  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Glucose Transporter ◽  
Contractile Function ◽  
Systolic Function ◽  
Cardiac Metabolism ◽  
Flow Measurements ◽  
Echocardiographic Assessment ◽  
Fractional Shortening

Control db/+ and diabetic db/ db mice at 6 and 12 wk of age were subjected to echocardiography to determine whether contractile function was reduced in vivo and restored in transgenic db/ db-human glucose transporter 4 (hGLUT4) mice (12 wk old) in which cardiac metabolism has been normalized. Systolic function was unchanged in 6-wk-old db/ db mice, but fractional shortening and velocity of circumferential fiber shortening were reduced in 12-wk-old db/ db mice (43.8 ± 2.1% and 8.3 ± 0.5 circs/s, respectively) relative to db/+ control mice (59.5 ± 2.3% and 11.8 ± 0.4 circs/s, respectively). Doppler flow measurements were unchanged in 6-wk-old db/ db mice. The ratio of E and A transmitral flows was reduced from 3.56 ± 0.29 in db/+ mice to 2.40 ± 0.20 in 12-wk-old db/ dbmice, indicating diastolic dysfunction. Thus a diabetic cardiomyopathy with systolic and diastolic dysfunction was evident in 12-wk-old diabetic db/ db mice. Cardiac function was normalized in transgenic db/ db-hGLUT4 mice, indicating that altered cardiac metabolism can produce contractile dysfunction in diabetic db/ db hearts.

scholarly journals The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

2014 ◽  
Vol 34 (7) ◽  
pp. 1233-1242 ◽  
Author(s):  
Golam MI Chowdhury ◽  
Lihong Jiang ◽  
Douglas L Rothman ◽  
Kevin L Behar
Keyword(s):  
Ketone Bodies ◽  
Ex Vivo ◽  
Brain Activity ◽  
Tca Cycle ◽  
Blood Levels ◽  
Neuronal Function ◽  
Energy Needs ◽  
Activity Dependent ◽  
Sufficient Concentration

The capacity of ketone bodies to replace glucose in support of neuronal function is unresolved. Here, we determined the contributions of glucose and ketone bodies to neocortical oxidative metabolism over a large range of brain activity in rats fasted 36 hours and infused intravenously with [2,4- 13 C2]-D-β-hydroxybutyrate (BHB). Three animal groups and conditions were studied: awake ex vivo, pentobarbital-induced isoelectricity ex vivo, and halothane-anesthetized in vivo, the latter data reanalyzed from a recent study. Rates of neuronal acetyl-CoA oxidation from ketone bodies ( VaccoA-kbN) and pyruvate ( VpdhN), and the glutamate-glutamine cycle ( Vcyc) were determined by metabolic modeling of 13C label trapped in major brain amino acid pools. VacCoA-kbN increased gradually with increasing activity, as compared with the steeper change in tricarboxylic acid (TCA) cycle rate ( VtcaN), supporting a decreasing percentage of neuronal ketone oxidation: ˜100% (isoelectricity), 56% (halothane anesthesia), 36% (awake) with the BHB plasma levels achieved in our experiments (6 to 13 mM). In awake animals ketone oxidation reached saturation for blood levels > 17 mM, accounting for 62% of neuronal substrate oxidation, the remainder (38%) provided by glucose. We conclude that ketone bodies present at sufficient concentration to saturate metabolism provides full support of basal (housekeeping) energy needs and up to approximately half of the activity-dependent oxidative needs of neurons.

Sign in / Sign up

Export Citation Format

Share Document