Metabolomic profiling of urinary changes in mice with monosodium glutamate-induced obesity
- 692 Downloads
Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor-gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months.
KeywordsMouse model Monosodium glutamate (MSG) induced obesity Diabetes NMR Metabolomics Urine
We are indebted to H. Vysušilová for her excellent technical assistance.
Compliance with ethical standards
The research was financially supported by the Czech Science Foundation (Grant No. GA13-14105S), grant for long-term conceptual development of the Institute of Microbiology (RVO: 61388971) and Institute of Organic Chemistry and Biochemistry (RVO: 61388963). The project was conducted within the “Prague Infrastructure for Structure Biology and Metabolomics” which has been built up by financial support of the Operational Program Prague – Competitiveness (Project No.: CZ.2.16/3.1.00/24023). The data analyses were partially supported by the Grant Agency of the Czech Technical University in Prague No. SGS13/203/OHK3/3T/13. We would also like to acknowledge project LO1509 of the Ministry of Education, Youth and Sports of the Czech Republic.
Conflict of interest
Helena Pelantová, Simona Bártová, Jiří Anýž, Martina Holubová, Blanka Železná, Lenka Maletínská, Daniel Novák, Zdena Lacinová, Miroslav Šulc, Martin Haluzík, and Marek Kuzma declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
- 5.Lutz TA, Woods SC (2012) Overview of animal models of obesity. Curr Protoc Pharmacol Chapter 5:Unit5.61. doi: 10.1002/0471141755.ph0561s58
- 8.Kim IY, Jung J, Jang M, Ahn YG, Shin JH, Choi JW, Sohn MR, Shin SM, Kang D-G, Lee H-S, Bae YS, Ryu DH, Seong JK, Hwang G-S (2010) 1H NMR-based metabolomic study on resistance to diet-induced obesity in AHNAK knock-out mice. Biochem Biophys Res Commun 403:428–434. doi: 10.1016/j.bbrc.2010.11.048 CrossRefGoogle Scholar
- 9.Boulangé CL, Claus SP, Chou CJ, Collino S, Montoliu I, Kochhar S, Holmes E, Rezzi S, Nicholson JK, Dumas ME, Martin F-PJ (2013) Early metabolic adaptation in C57BL/6 mice resistant to high fat diet induced weight gain involves an activation of mitochondrial oxidative pathways. J Proteome Res 12:1956–1968. doi: 10.1021/pr400051s CrossRefGoogle Scholar
- 13.Graham ML, Janecek JL, Kittredge JA, Hering BJ, Schuurman H-J (2011) The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. Comp Med 61:356–360Google Scholar
- 17.Broberger C, De Lecea L, Sutcliffe JG, Hökfelt T (1998) Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402:460–474. doi: 10.1002/(SICI)1096-9861(19981228)402:4<460::AID-CNE3>3.0.CO;2-S CrossRefGoogle Scholar
- 19.Zelezná B, Maixnerová J, Matysková R, Haugvicová R, Blokesová D, Maletínská L (2009) Anorexigenic effect of cholecystokinin is lost but that of CART (Cocaine and Amphetamine Regulated Transcript) peptide is preserved in monosodium glutamate obese mice. Physiol Res 58:717–723Google Scholar
- 25.Matyšková R, Maletínská L, Maixnerová J, Pirník Z, Kiss A, Železná B (2008) Comparison of the obesity phenotypes related to monosodium glutamate effect on arcuate nucleus and/or the high fat diet feeding in C57BL/6 and NMRI mice. Physiol Res 57:727–734Google Scholar
- 26.Hernández-Bautista RJ, Alarcón-Aguilar FJ, Del C, Escobar-Villanueva M, Almanza-Pérez JC, Merino-Aguilar H, Fainstein MK, López-Diazguerrero NE (2014) Biochemical alterations during the obese-aging process in female and male monosodium glutamate (MSG)-treated mice. Int J Mol Sci 15:11473–11494. doi: 10.3390/ijms150711473 CrossRefGoogle Scholar
- 27.Roman-Ramos R, Almanza-Perez JC, Garcia-Macedo R, Blancas-Flores G, Fortis-Barrera A, Jasso EI, Garcia-Lorenzana M, Campos-Sepulveda AE, Cruz M, Alarcon-Aguilar FJ (2011) Monosodium glutamate neonatal intoxication associated with obesity in adult stage is characterized by chronic inflammation and increased mRNA expression of peroxisome proliferator-activated receptors in mice. Basic Clin Pharmacol Toxicol 108:406–413. doi: 10.1111/j.1742-7843.2011.00671.x CrossRefGoogle Scholar
- 28.Maletínská L, Matyšková R, Maixnerová J, Sýkora D, Pýchová M, Spolcová A, Blechová M, Drápalová J, Lacinová Z, Haluzík M, Zelezná B (2011) The Peptidic GHS-R antagonist [D-Lys(3)]GHRP-6 markedly improves adiposity and related metabolic abnormalities in a mouse model of postmenopausal obesity. Mol Cell Endocrinol 343:55–62. doi: 10.1016/j.mce.2011.06.006 CrossRefGoogle Scholar
- 30.(2013) MATLAB version 22.214.171.1244 (R2013a). Natick, Massachusetts: The MathWorks IncGoogle Scholar
- 34.Salek RM, Maguire ML, Bentley E, Rubtsov DV, Hough T, Cheeseman M, Nunez D, Sweatman BC, Haselden JN, Cox RD, Connor SC, Griffin JL (2007) A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiol Genomics 29:99–108. doi: 10.1152/physiolgenomics.00194.2006 CrossRefGoogle Scholar
- 35.Ringeissen S, Connor SC, Brown HR, Sweatman BC, Hodson MP, Kenny SP, Haworth RI, McGill P, Price MA, Aylott MC, Nunez DJ, Haselden JN, Waterfield CJ (2003) Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography. Biomarkers 8:240–271. doi: 10.1080/1354750031000149124 CrossRefGoogle Scholar
- 36.Delaney J, Hodson MP, Thakkar H, Connor SC, Sweatman BC, Kenny SP, McGill PJ, Holder JC, Hutton KA, Haselden JN, Waterfield CJ (2005) Tryptophan-NAD+ pathway metabolites as putative biomarkers and predictors of peroxisome proliferation. Arch Toxicol 79:208–223. doi: 10.1007/s00204-004-0625-5 CrossRefGoogle Scholar
- 39.Pirinen E, Kuulasmaa T, Pietilä M, Heikkinen S, Tusa M, Itkonen P, Boman S, Skommer J, Virkamäki A, Hohtola E, Kettunen M, Fatrai S, Kansanen E, Koota S, Niiranen K, Parkkinen J, Levonen A-L, Ylä-Herttuala S, Hiltunen JK, Alhonen L, Smith U, Jänne J, Laakso M (2007) Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism. Mol Cell Biol 27:4953–4967. doi: 10.1128/MCB.02034-06 CrossRefGoogle Scholar
- 40.Jell J, Merali S, Hensen ML, Mazurchuk R, Spernyak JA, Diegelman P, Kisiel ND, Barrero C, Deeb KK, Alhonen L, Patel MS, Porter CW (2007) Genetically altered expression of spermidine/spermine N1-acetyltransferase affects fat metabolism in mice via acetyl-CoA. J Biol Chem 282:8404–8413. doi: 10.1074/jbc.M610265200 CrossRefGoogle Scholar
- 42.Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, Pirinen E, Pulinilkunnil TC, Gong F, Wang Y, Cen Y, Sauve AA, Asara JM, Peroni OD, Monia BP, Bhanot S, Alhonen L, Puigserver P, Kahn BB (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508:258–262. doi: 10.1038/nature13198 CrossRefGoogle Scholar
- 44.Hui X, Zhu W, Wang Y, Lam KSL, Zhang J, Wu D, Kraegen EW, Li Y, Xu A (2009) Major urinary protein-1 increases energy expenditure and improves glucose intolerance through enhancing mitochondrial function in skeletal muscle of diabetic mice. J Biol Chem 284:14050–14057. doi: 10.1074/jbc.M109.001107 CrossRefGoogle Scholar
- 48.Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Gallup D, Ilkayeva O, Wenner BR, Yancy WE, Musante G, Surwit R, Millington DS, Butler MD, Laura P (2013) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:311–326. doi: 10.1016/j.cmet.2009.02.002.A CrossRefGoogle Scholar
- 51.Yardim-Akaydin S, Sepici A, Ozkan Y, Simşek B, Sepici V. Evaluation of allantoin levels as a new marker of oxidative stress in Behçet’s disease. Scand J Rheumatol 35:61–64. doi: 10.1080/03009740510026878
- 54.Fukuhara K, Ohno A, Ota Y, Senoo Y, Maekawa K, Okuda H, Kurihara M, Okuno A, Niida S, Saito Y, Takikawa O (2013) NMR-based metabolomics of urine in a mouse model of Alzheimer’s disease: identification of oxidative stress biomarkers. J Clin Biochem Nutr 52:133–138. doi: 10.3164/jcbn.12-118 CrossRefGoogle Scholar