Changes in metabolite profiles caused by genetically determined obesity in mice.
The Berlin Fat Mouse Inbred (BFMI) line harbors a major recessive gene defect on chromosome 3 (jobes1) leading to juvenile obesity and metabolic syndrome. The present study aimed at the identification of metabolites that might be linked to recessively acting genes in the obesity locus. Firstly, serum metabolites were analyzed between obese BFMI and lean B6 and BFMI × B6 F1mice to identify metabolites that are different. In a second step, a metabolite-protein network analysis was performed linking metabolites typical for BFMI mice with genes of thejobes1region. The levels of 22 diacyl-phosphatidylcholines (PC aa), two lyso-PC and three carnitines were found to be significantly lower in obese mice compared with lean mice, while serine, glycine, arginine and hydroxysphingomyelin were higher for the same comparison. The network analysis identified PC aa C42:1 as functionally linked with the genesCcna2andTrpc3via the enzymes choline kinase alpha and phospholipase A2 group 1B (PLA2G1B), respectively. Gene expression analysis revealed elevatedCcna2expression in adipose tissue of BFMI mice. Furthermore, unique mutations were found in theCcna2promoter of BFMI mice which are located in binding sites for transcription factors or micro RNAs and could cause differentialCcna2mRNA levels between BFMI and B6 mice. Increased expression ofCcna2was consistent with higher mitotic activity of adipose tissue in BFMI mice. Therefore, we suggest a higher demand for PC necessary for adipose tissue growth and remodeling. This study highlights the relationship between metabolite profiles and the underlying genetics of obesity in the BFMI line.
Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany.|The Institute for Research in Operative Medicine, Faculty of Health, Department of Medicine, Witten/Herdecke University, Ostmerheimer Str. 200, 51109 Cologne, Germany.
Nadine
N
Schäfer
Research Unit of Molecular Epidemiology, Helmholtz-Zentrum München (GmbH), German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Munich/Neuherberg, Germany.
Zhonghao
Z
Yu
Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany.
Asja
A
Wagener
Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany.
Marion K
MK
Millrose
Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany.
Monika
M
Reissmann
Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany.
Ralf
R
Bortfeldt
Berlin Institute for Medical Systems Biology at the Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Str. 10, 13125 Berlin, Germany.
Christoph
C
Dieterich
Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Jerzy
J
Adamski
Research Unit of Molecular Epidemiology, Helmholtz-Zentrum München (GmbH), German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Munich/Neuherberg, Germany.
Rui
R
Wang-Sattler
Research Unit of Molecular Epidemiology, Helmholtz-Zentrum München (GmbH), German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Munich/Neuherberg, Germany.|Hannover Unified Biobank, Medical School Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Thomas
T
Illig
Breeding Biology and Molecular Genetics, Department for Crop and Animal Sciences, Humboldt-Universität zu Berlin, Invalidenstr. 42, 10115 Berlin, Germany.
Gudrun A
GA
Brockmann
Adiposity; Metabolism; Phosphatidylcholine