title: The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice.
abstract: Calorie restriction (CR) remains the most robust intervention to extend lifespan and improve health span. Using a global mass spectrometry-based metabolomic approach, we identified 193 metabolites that were significantly differentially expressed (SDE) in the livers of C57BL/6 mice, fed graded levels of CR (10, 20, 30 and 40% CR) compared to mice fed ad libitum for 12 h a day. The differential expression of metabolites also varied with the different feeding groups. Pathway analysis revealed that graded CR had an impact on carnitine synthesis and the carnitine shuttle pathway, sphingosine-1-phosphate (S1P) signalling and methionine metabolism. S1P, sphingomyelin and L-carnitine were negatively correlated with body mass, leptin, insulin-like growth factor- 1 (IGF-1) and major urinary proteins (MUPs). In addition, metabolites which showed a graded effect, such as ceramide, S1P, taurocholic acid and L-carnitine, responded in the opposite direction to previously observed age-related changes. We suggest that the modulation of this set of metabolites may improve liver processes involved in energy release from fatty acids. S1P also negatively correlated with catalase activity and body temperature, and positively correlated with food anticipatory activity. Injecting mice with S1P or an S1P receptor 1 agonist did not precipitate changes in body temperature, physical activity or food intake suggesting that these correlations were not causal relationships.
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Green
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Mitchell
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Davina
authors.initials: D
authors.lastname: Derous
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Luonan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jing-Dong J
authors.initials: JJ
authors.lastname: Han
authors.affiliation: Department of Pathology and Department of Biology, University of Washington, Seattle, WA, USA.
authors.forename: Daniel E L
authors.initials: DEL
authors.lastname: Promislow
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lusseau
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Douglas
authors.affiliation: Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.|State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Chaoyang, Beijing, China.
authors.forename: John R
authors.initials: JR
authors.lastname: Speakman
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D031204:Caloric Restriction; D002331:Carnitine / Q000378:metabolism*; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008246:Lysophospholipids / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D020738:Leptin; D008246:Lysophospholipids; D011506:Proteins; D049349:Receptors, Lysosphingolipid; D013107:Sphingolipids; C035737:major urinary proteins; C060506:sphingosine 1-phosphate; D007334:Insulin-Like Growth Factor I; D008715:Methionine; D002374:Catalase; D013110:Sphingosine; D002331:Carnitine
keywords: Metabolomics; aging; bile acid; calorie restriction; carnitine; sphingolipid