For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
46
views
171
references
 Top references
cited by
112
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      401
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Regulation of Ketone Body Metabolism and the Role of PPARα

      review-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Ketogenesis and ketolysis are central metabolic processes activated during the response to fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor α (PPARα) is one of the key transcription factors taking part in this regulation. PPARα is an important element in the metabolic network, where it participates in signaling driven by the main nutrient sensors, such as AMP-activated protein kinase (AMPK), PPARγ coactivator 1α (PGC-1α), and mammalian (mechanistic) target of rapamycin (mTOR) and induces hormonal mediators, such as fibroblast growth factor 21 (FGF21). This work describes the regulation of ketogenesis and ketolysis in normal and malignant cells and briefly summarizes the positive effects of ketone bodies in various neuropathologic conditions.

          Related collections

          Most cited references171

          • Record: found
          • Abstract: found
          • Article: not found

          Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

          Ikuo Kimura, Daisuke Inoue, Takeshi Maeda … (2011)
          The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
          Article 0 comments Cited 386 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting.

            S. Kersten, J. Seydoux, J Peters … (1999)
            Prolonged deprivation of food induces dramatic changes in mammalian metabolism, including the release of large amounts of fatty acids from the adipose tissue, followed by their oxidation in the liver. The nuclear receptor known as peroxisome proliferator-activated receptor alpha (PPARalpha) was found to play a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that PPARalpha may be involved in the transcriptional response to fasting. To investigate this possibility, PPARalpha-null mice were subjected to a high fat diet or to fasting, and their responses were compared with those of wild-type mice. PPARalpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. A similar phenotype was noted in PPARalpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It is shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPARalpha mRNA is induced during fasting in wild-type mice. The data indicate that PPARalpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPARalpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.
            Article 0 comments Cited 382 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The PPARalpha-leukotriene B4 pathway to inflammation control.

              P R Devchand, H. Keller, J Peters … (1996)
              Inflammation is a local immune response to 'foreign' molecules, infection and injury. Leukotriene B4, a potent chemotactic agent that initiates, coordinates, sustains and amplifies the inflammatory response, is shown to be an activating ligand for the transcription factor PPARalpha. Because PPARalpha regulates the oxidative degradation of fatty acids and their derivatives, like this lipid mediator, a feedback mechanism is proposed that controls the duration of an inflammatory response and the clearance of leukotriene B4 in the liver. Thus PPARalpha offers a new route to the development of anti- or pro-inflammatory reagents.
              Article 0 comments Cited 232 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Béatrice Desvergne: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 13 December 2016
                Publication date Collection: December 2016
                Volume: 17
                Issue: 12
                Electronic Location Identifier: 2093
                Affiliations
                [1 ]Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Balicka 122, 30-149 Kraków, Poland; m.pierzchalska@ 123456ur.krakow.pl
                [2 ]Neurological Cancer Research, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, 1700 Tulane Ave, New Orleans, LA 70112, USA; mdean3@ 123456lsuhsc.edu (M.D.); kreiss@ 123456lsuhsc.edu (K.R.)
                Author notes
                [* ]Correspondence: m.grabacka@ 123456ur.krakow.pl ; Tel.: +48-12-662-4796
                Article
                Publisher ID: ijms-17-02093
                DOI: 10.3390/ijms17122093
                PMC ID: 5187893
                PubMed ID: 27983603
                SO-VID: 092dd751-4a22-4fc9-98dc-b0f875682e1c
                Copyright © © 2016 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 23 September 2016
                Date accepted : 07 December 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: β hydroxybutyrate,3-hydroxy-3-methylglytaryl-coa synthetase 2 (hmgcs2),fenofibrate,melanoma,glioma,fasting
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: β hydroxybutyrate, 3-hydroxy-3-methylglytaryl-coa synthetase 2 (hmgcs2), fenofibrate, melanoma, glioma, fasting

                Comments

                Comment on this article

                scite_

                Similar content401

                See all similar

                Cited by110

                See all cited by

                Most referenced authors2,603

                See all reference authors