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The Effects of Ketones on Metabolic Function
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The Effects of Ketones on Metabolic Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 47045

Special Issue Editors

Dr. Benjamin T. Bikman

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Guest Editor
Associate Professor, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
Interests: effects of insulin; ketones on cellular metabolism; mitochondrial function
Special Issues, Collections and Topics in MDPI journals
Dr. Paul R. Reynolds

E-Mail Website
Guest Editor
Associate Professor, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
Interests: mechanisms of pulmonary injury and disease related to oxidative stress
Special Issues, Collections and Topics in MDPI journals
Dr. Daniel A. Kane

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Guest Editor
Associate Professor, Department of Human Kinetics, St. Francis Xavier University, Antigonish, Nova Scotia, Canada
Interests: mitochondrial bioenergetics, exercise and monocarboxylate metabolism
Dr. Katsu Funai

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Guest Editor
Assistant Professor, Department of Physical Therapy & Athletic Training / Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
Interests: intracellular fate of lipids into cellular membranes

Special Issue Information

Dear Colleagues,

Once considered “metabolic garbage”, ketones have become the focus of significant efforts within the realm of cardiometabolic research. Recent discoveries have revealed that ketones, such as acetoacetate and its precursor β-hydroxybutyrate (β-HB), are not only viable fuel sources for all cells with mitochondria, including the brain, but are also legitimate signaling molecules, eliciting advantageous changes in inflammation, cognition, oxidative stress, and more. Beyond pathology, ketones may also be a relevant metabolic fuel in the context of physical activity, insofar as ketone-adapted athletes appear to outperform conventional glucose-adapted athletes. Whether through diets sufficiently low in carbohydrate consumption to induce hepatic ketogenesis or the consumption of exogenous ketones, limited evidence suggests a generally favorable metabolic milieu.

We invite authors to contribute original research articles, as well as review articles that will illustrate and stimulate the blossoming effort to understand the role of ketones in diverse metabolic models and conditions. The accepted papers will highlight to readers the metabolic relevance of ketones and, thus, potentially provide a new paradigm on the role of ketones in altering cellular function.

Dr. Benjamin T. Bikman
Dr. Paul R. Reynolds
Dr. Daniel A. Kane
Dr. Katsu Funai
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (4 papers)

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Research

10 pages, 4129 KiB  
Communication
A Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer’s Disease
by Robert J. Pawlosky, Yoshihero Kashiwaya, M. Todd King and Richard L. Veech
Int. J. Mol. Sci. 2020, 21(3), 1044; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031044 - 04 Feb 2020
Cited by 24 | Viewed by 5647
Abstract
Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s [...] Read more.
Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s disease (AD), aging mice also demonstrate low brain glucose metabolism. Ketone metabolism can overcome PDH inhibition and restore TCA cycle metabolites, thereby enhancing amino acid biosynthesis. A ketone ester of d-β-hydroxybutyrate was incorporated into a diet (Ket) and fed to 3xTgAd mice. A control group was fed a calorically matched diet (Cho). At 15 months of age, the exploratory and avoidance-related behavior patterns of the mice were evaluated. At 16.5 months of age, the animals were euthanized, and their hippocampi were analyzed for citrate, α-ketoglutarate, and amino acids. In the hippocampi of the Ket-fed mice, there were higher concentrations of citrate and α-ketoglutarate as well as higher concentrations of glutamate, aspartate and n-acetyl-aspartate compared with controls. There were positive associations between (1) concentrations of aspartate and n-acetyl-aspartate (n = 14, R = 0.9327), and (2) α-ketoglutarate and glutamate (n = 14, R = 0.8521) in animals maintained on either diet. Hippocampal n-acetyl-aspartate predicted the outcome of several exploratory and avoidance-related behaviors. Ketosis restored citrate and α-ketoglutarate in the hippocampi of aging mice. Higher concentrations of n-acetyl-aspartate corresponded with greater exploratory activity and reduced avoidance-related behavior. Full article
(This article belongs to the Special Issue The Effects of Ketones on Metabolic Function)
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18 pages, 2923 KiB  
Article
Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models
by David Licha, Silvia Vidali, Sepideh Aminzadeh-Gohari, Oliver Alka, Leander Breitkreuz, Oliver Kohlbacher, Roland J. Reischl, René G. Feichtinger, Barbara Kofler and Christian G. Huber
Int. J. Mol. Sci. 2019, 20(16), 3873; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20163873 - 08 Aug 2019
Cited by 21 | Viewed by 7166
Abstract
The application of ketogenic diet (KD) (high fat/low carbohydrate/adequate protein) as an auxiliary cancer therapy is a field of growing attention. KD provides sufficient energy supply for healthy cells, while possibly impairing energy production in highly glycolytic tumor cells. Moreover, KD regulates insulin [...] Read more.
The application of ketogenic diet (KD) (high fat/low carbohydrate/adequate protein) as an auxiliary cancer therapy is a field of growing attention. KD provides sufficient energy supply for healthy cells, while possibly impairing energy production in highly glycolytic tumor cells. Moreover, KD regulates insulin and tumor related growth factors (like insulin growth factor-1, IGF-1). In order to provide molecular evidence for the proposed additional inhibition of tumor growth when combining chemotherapy with KD, we applied untargeted quantitative metabolome analysis on a spontaneous breast cancer xenograft mouse model, using MDA-MB-468 cells. Healthy mice and mice bearing breast cancer xenografts and receiving cyclophosphamide chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of adjuvant KD in the context of tumor growth inhibition and suggest additional mechanisms of tumor suppression beyond the proposed constrain in energy supply of tumor cells. Full article
(This article belongs to the Special Issue The Effects of Ketones on Metabolic Function)
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10 pages, 1239 KiB  
Communication
Lithium and Not Acetoacetate Influences the Growth of Cells Treated with Lithium Acetoacetate
by Silvia Vidali, Sepideh Aminzadeh-Gohari, Renaud Vatrinet, Luisa Iommarini, Anna Maria Porcelli, Barbara Kofler and René Günther Feichtinger
Int. J. Mol. Sci. 2019, 20(12), 3104; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20123104 - 25 Jun 2019
Cited by 10 | Viewed by 4530
Abstract
The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated [...] Read more.
The ketogenic diet (KD), a high-fat/low-carbohydrate/adequate-protein diet, has been proposed as a treatment for a variety of diseases, including cancer. KD leads to generation of ketone bodies (KBs), predominantly acetoacetate (AcAc) and 3-hydroxy-butyrate, as a result of fatty acid oxidation. Several studies investigated the antiproliferative effects of lithium acetoacetate (LiAcAc) and sodium 3-hydroxybutyrate on cancer cells in vitro. However, a critical point missed in some studies using LiAcAc is that Li ions have pleiotropic effects on cell growth and cell signaling. Thus, we tested whether Li ions per se contribute to the antiproliferative effects of LiAcAc in vitro. Cell proliferation was analyzed on neuroblastoma, renal cell carcinoma, and human embryonic kidney cell lines. Cells were treated for 5 days with 2.5, 5, and 10 mM LiAcAc and with equimolar concentrations of lithium chloride (LiCl) or sodium chloride (NaCl). LiAcAc affected the growth of all cell lines, either negatively or positively. However, the effects of LiAcAc were always similar to those of LiCl. In contrast, NaCl showed no effects, indicating that the Li ion impacts cell proliferation. As Li ions have significant effects on cell growth, it is important for future studies to include sources of Li ions as a control. Full article
(This article belongs to the Special Issue The Effects of Ketones on Metabolic Function)
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12 pages, 2192 KiB  
Article
β-Hydroxybutyrate Elicits Favorable Mitochondrial Changes in Skeletal Muscle
by Brian A. Parker, Chase M. Walton, Sheryl T. Carr, Jacob L. Andrus, Eric C. K. Cheung, Michael J. Duplisea, Esther K. Wilson, Carrie Draney, Daniel R. Lathen, Kyle B. Kenner, David M. Thomson, Jeffery S. Tessem and Benjamin T. Bikman
Int. J. Mol. Sci. 2018, 19(8), 2247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082247 - 01 Aug 2018
Cited by 29 | Viewed by 26525
Abstract
The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose [...] Read more.
The clinical benefit of ketosis has historically and almost exclusively centered on neurological conditions, lending insight into how ketones alter mitochondrial function in neurons. However, there is a gap in our understanding of how ketones influence mitochondria within skeletal muscle cells. The purpose of this study was to elucidate the specific effects of β-hydroxybutyrate (β-HB) on muscle cell mitochondrial physiology. In addition to increased cell viability, murine myotubes displayed beneficial mitochondrial changes evident in reduced H2O2 emission and less mitochondrial fission, which may be a result of a β-HB-induced reduction in ceramides. Furthermore, muscle from rats in sustained ketosis similarly produced less H2O2 despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity. In sum, these results indicate a general improvement in muscle cell mitochondrial function when β-HB is provided as a fuel. Full article
(This article belongs to the Special Issue The Effects of Ketones on Metabolic Function)
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