Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes

Frontiers in Microbiology

Volumn 6, Issue OCT, 2015, Pages

  Palau Rodriguez, Magali ^a   Tulipani, Sara ^a,b   Queipo Ortuño, Maria Isabel ^b,c   Urpi Sarda, Mireia ^a   Tinahones, Francisco J ^b,c   Andres Lacueva, Cristina ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

^b UNIVERSITY OF MÁLAGA   (Spain)

^c Instituto de Salud Carlos III   (Spain)

Author keywords

Co metabolism; Gut microbiota; Metabolomics; Obesity; Type 2 diabetes

Indexed keywords

1 METHYLURIC ACID; 2 HYDROXYISOBUTYRATE; 3 HYDROXYHIPPURIC ACID; CARBOXYLIC ACID; CARNITINE; CHOLINE; HIPPURIC ACID; METFORMIN; METHYLXANTHINE; NICOTINIC ACID; PLANT MEDICINAL PRODUCT; SULFONYLUREA; TRIGONELLINE; UNCLASSIFIED DRUG;

ACTINOBACTERIA; BACTEROIDETES; BILE ACID METABOLISM; BODY MASS; CLOSTRIDIUM; DYSBIOSIS; FAECALIBACTERIUM PRAUSNITZII; FIRMICUTES; GLUCOSE HOMEOSTASIS; HUMAN; INSULIN RESISTANCE; INTESTINE FLORA; METABOLITE; METABOLOMICS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ORGANISMAL INTERACTION; OXIDATIVE STRESS; PROTEOBACTERIA; PURINE METABOLISM; REVIEW; SPECIES COMPOSITION; VITAMIN METABOLISM;

EID: 84946830070     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2015.01151     Document Type: Review

References (86)

1. Astrup, A., and Finer, N. (2000). Redefining type 2 diabetes: "diabesity" or "obesity dependent diabetes mellitus"? Obes. Rev. 1, 57-59. doi: 10.1046/j.1467-789x.2000.00013.x
2. Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A., and Gordon, J. I. (2005). Host-bacterial mutualism in the human intestine. Science 307, 1915-1920. doi: 10.1126/science.1104816
3. Bäckhed, F., Manchester, J. K., Semenkovich, C. F., and Gordon, J. I. (2007). Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. U.S.A. 104, 979-984. doi: 10.1073/pnas.0605374104
4. Beckonert, O., Coen, M., Keun, H. C., Wang, Y., Ebbels, T. M. D., Holmes, E., et al. (2010). High-resolution magic-angle-spinning NMR spectroscopy for metabolic profiling of intact tissues. Nat. Protoc. 5, 1019-1032. doi: 10.1038/nprot.2010.45
5. Begley, M., Gahan, C. G. M., and Hill, C. (2005). The interaction between bacteria and bile. FEMS Microbiol. Rev. 29, 625-651. doi: 10.1016/j.femsre.2004.09.003
6. Blusztajn, J. K. (1998). Choline, a vital amine. Science 281, 794-795. doi: 10.1126/science.281.5378.794
7. Calvani, R., Miccheli, A., Capuani, G., Tomassini Miccheli, A., Puccetti, C., Delfini, M., et al. (2010). Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype. Int. J. Obes. (Lond.) 34, 1095-1098. doi: 10.1038/ijo.2010.44
8. Campbell, C., Grapov, D., Fiehn, O., Chandler, C. J., Burnett, D. J., Souza, E. C., et al. (2014). Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS ONE 9:e84260. doi: 10.1371/journal.pone.0084260
9. Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., et al. (2007). Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761-1772. doi: 10.2337/db06-1491
10. Cani, P. D., Osto, M., Geurts, L., and Everard, A. (2012). Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity. Gut Microbes 3, 279-288. doi: 10.4161/gmic.19625
11. Craciun, S., and Balskus, E. P. (2012). Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc. Natl. Acad. Sci. U.S.A. 109, 21307-21312. doi: 10.1073/pnas.1215689109
12. Delzenne, N. M., and Cani, P. D. (2011). Interaction between obesity and the gut microbiota: relevance in nutrition. Annu. Rev. Nutr. 31, 15-31. doi: 10.1146/annurev-nutr-072610-145146
13. Dewulf, E. M., Cani, P. D., Claus, S. P., Fuentes, S., Puylaert, P. G. B., Neyrinck, A. M., et al. (2013). Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women. Gut 62, 1112-1121. doi: 10.1136/gutjnl-2012-303304
14. DiBaise, J. K., Zhang, H., Crowell, M. D., Krajmalnik-Brown, R., Decker, G. A., and Rittmann, B. E. (2008). Gut microbiota and its possible relationship with obesity. Mayo Clin. Proc. 83, 460-469. doi: 10.4065/83.4.460
15. Du, F., Virtue, A., Wang, H., and Yang, X.-F. (2013). Metabolomic analyses for atherosclerosis, diabetes, and obesity. Biomark. Res. 1:17. doi: 10.1186/2050-7771-1-17
16. Dumas, M.-E., Barton, R. H., Toye, A., Cloarec, O., Blancher, C., Rothwell, A., et al. (2006). Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl. Acad. Sci. U.S.A. 103, 12511-12516. doi: 10.1073/pnas.0601056103
17. Duncan, S. H., Holtrop, G., Lobley, G. E., Calder, A. G., Stewart, C. S., and Flint, H. J. (2004). Contribution of acetate to butyrate formation by human faecal bacteria. Br. J. Nutr. 91, 915-923. doi: 10.1079/BJN20041150
18. Faber, J. H., Malmodin, D., Toft, H., Maher, A. D., Crockford, D., Holmes, E., et al. (2007). Metabonomics in diabetes research. J. Diabetes Sci. Technol. 1, 549-557. doi: 10.1177/193229680700100413
19. Fukiya, S., Arata, M., Kawashima, H., Yoshida, D., Kaneko, M., Minamida, K., et al. (2009). Conversion of cholic acid and chenodeoxycholic acid into their 7-oxo derivatives by Bacteroides intestinalis AM-1 isolated from human feces. FEMS Microbiol. Lett. 293, 263-270. doi: 10.1111/j.1574-6968.2009.01531.x
20. Gibson, G. R., Scott, K. P., Rastall, R. A., Tuohy, K. M., Hotchkiss, A., Dubert-Ferrandon, A., et al. (2010). Dietary prebiotics: current status and new definition. Food Sci. Technol. Bull. Funct. Foods 7, 1-19. doi: 10.1616/1476-2137.15880
21. Gipson, G. T., Tatsuoka, K. S., Ball, R. J., Sokhansanj, B. A., Hansen, M. K., Ryan, T. E., et al. (2008). Multi-platform investigation of the metabolome in a leptin receptor defective murine model of type 2 diabetes. Mol. Biosyst. 4, 1015-1023. doi: 10.1039/b807332e
22. Guan, M., Xie, L., Diao, C., Wang, N., Hu, W., Zheng, Y., et al. (2013). Systemic perturbations of key metabolites in diabetic rats during the evolution of diabetes studied by urine metabonomics. PLoS ONE 8:e60409. doi: 10.1371/journal.pone.0060409
23. Hadacek, F. (2015). Low-molecular-weight metabolite systems chemistry. Front. Environ. Sci. 3:12. doi: 10.3389/fenvs.2015.00012
24. Harris, K., Kassis, A., Major, G., and Chou, C. J. (2012). Is the gut microbiota a new factor contributing to obesity and its metabolic disorders? J. Obes. 2012:879151. doi: 10.1155/2012/879151
25. Hofmann, A. F., and Hagey, L. R. (2008). Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics. Cell. Mol. Life Sci. 65, 2461-2483. doi: 10.1007/s00018-008-7568-6
26. Hosseini, E., Grootaert, C., Verstraete, W., and Van de Wiele, T. (2011). Propionate as a health-promoting microbial metabolite in the human gut. Nutr. Rev. 69, 245-258. doi: 10.1111/j.1753-4887.2011.00388.x
27. Hu, F. B., Manson, J. E., Stampfer, M. J., Colditz, G., Liu, S., Solomon, C. G., et al. (2001). Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N. Engl. J. Med. 345, 790-797. doi: 10.1056/NEJMoa010492
28. Huang, C.-F., Cheng, M.-L., Fan, C.-M., Hong, C.-Y., and Shiao, M.-S. (2012). Nicotinuric acid: a potential marker of metabolic syndrome through a metabolomics-based approach. Diabetes Care 36, 1729-1731. doi: 10.2337/dc12-1067
29. Huo, T., Cai, S., Lu, X., Sha, Y., Yu, M., and Li, F. (2009). Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride. J. Pharm. Biomed. Anal. 49, 976-982. doi: 10.1016/j.jpba.2009.01.008
30. Huo, T., Xiong, Z., Lu, X., and Cai, S. (2015). Metabonomic study of biochemical changes in urinary of type 2 diabetes mellitus patients after the treatment of sulfonylurea antidiabetic drugs based on ultra-performance liquid chromatography/mass spectrometry. Biomed. Chromatogr. 29, 115-122. doi: 10.1002/bmc.3247
31. Jones, M. L., Martoni, C. J., Ganopolsky, J. G., Labbé, A., and Prakash, S. (2014). The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention. Exp. Opin. Biol. Ther. 14, 467-482. doi: 10.1517/14712598.2014.880420
32. Kawamata, Y., Fujii, R., Hosoya, M., Harada, M., Yoshida, H., Miwa, M., et al. (2003). A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435-9440. doi: 10.1074/jbc.M209706200
33. Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., et al. (2013). Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576-585. doi: 10.1038/nm.3145
34. Kootte, R. S., Vrieze, A., Holleman, F., Dallinga-Thie, G. M., Zoetendal, E. G., de Vos, W. M., et al. (2012). The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obes. Metab. 14, 112-120. doi: 10.1111/j.1463-1326.2011.01483.x
35. Kurland, I. J., Accili, D., Burant, C., Fischer, S. M., Kahn, B. B., Newgard, C. B., et al. (2013). Application of combined omics platforms to accelerate biomedical discovery in diabesity. Ann. N. Y. Acad. Sci. 1287, 1-16. doi: 10.1111/nyas.12116
36. Labbé, A., Ganopolsky, J. G., Martoni, C. J., Prakash, S., and Jones, M. L. (2014). Bacterial bile metabolising gene abundance in crohn's, ulcerative colitis and type 2 diabetes metagenomes. PLoS ONE 9:e115175. doi: 10.1371/journal.pone.0115175
37. Larsen, N., Vogensen, F. K., van den Berg, F. W. J., Nielsen, D. S., Andreasen, A. S., Pedersen, B. K., et al. (2010). Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE 5:e9085. doi: 10.1371/journal.pone.0009085
38. Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., and Staels, B. (2009). Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89, 147-191. doi: 10.1152/physrev.00010.2008
39. Lever, M., and Slow, S. (2010). The clinical significance of betaine, an osmolyte with a key role in methyl group metabolism. Clin. Biochem. 43, 732-744. doi: 10.1016/j.clinbiochem.2010.03.009
40. Ley, R. E., Bäckhed, F., Turnbaugh, P., Lozupone, C. A., Knight, R. D., and Gordon, J. I. (2005). Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. U.S.A. 102, 11070-11075. doi: 10.1073/pnas.0504978102
41. Ley, R. E., Turnbaugh, P. J., Klein, S., and Gordon, J. I. (2006). Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022-1023. doi: 10.1038/4441022a
42. Li, M., Wang, B., Zhang, M. M., Rantalainen, M., Wang, S., Zhou, H., et al. (2008). Symbiotic gut microbes modulate human metabolic phenotypes. Proc. Natl. Acad. Sci. U.S.A. 105, 2117-2122. doi: 10.1073/pnas.0712038105
43. Llorach, R., Garcia-Aloy, M., Tulipani, S., Vazquez-fresno, R., and Andres-lacueva, C. (2012). Nutrimetabolomic strategies to develop new biomarkers of intake and health effects. J. Agric. Food Chem. 60, 8797-8808. doi: 10.1021/jf301142b
44. Messana, I., Forni, F., Ferrari, F., Rossi, C., Giardina, B., and Zuppi, C. (1998). Proton nuclear magnetic resonance spectral profiles of urine in type II diabetic patients. Clin. Chem. 44, 1529-1534.
45. Micha, R., Wallace, S. K., and Mozaffarian, D. (2010). Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis. Circulation 121, 2271-2283. doi: 10.1161/CIRCULATIONAHA.109.924977
46. Midtvedt, T. (1974). Microbial bile acid. Am. J. Clin. Nutr. 27, 1341-1347.
47. Mokdad, A. H., Ford, E. S., Bowman, B. A., Dietz, W. H., Vinicor, F., Bales, V. S., et al. (2003). Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289, 76-79. doi: 10.1001/jama.289.1.76
48. Moreno-Indias, I., Cardona, F., Tinahones, F. J., and Queipo-Ortuño, M. I. (2014). Impact of the gut microbiota on the development of obesity and type 2 diabetes mellitus. Front. Microbiol. 5:190. doi: 10.3389/fmicb.2014.00190
49. Moreno-Navarrete, J. M., Ortega, F., Serino, M., Luche, E., Waget, A., Pardo, G., et al. (2012). Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance. Int. J. Obes. (Lond.) 36, 1442-1449. doi: 10.1038/ijo.2011.256
50. Musso, G., Gambino, R., and Cassader, M. (2010). Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded? Diabetes Care 33, 2277-2284. doi: 10.2337/dc10-0556
51. Nguyen, A., and Bouscarel, B. (2008). Bile acids and signal transduction: role in glucose homeostasis. Cell. Signal. 20, 2180-2197. doi: 10.1016/j.cellsig.2008.06.014
52. Nicholson, J. K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., et al. (2012). Host-gut microbiota metabolic interactions. Science 336, 1262-1267. doi: 10.1126/science.1223813
53. Piche, T., des Varannes, S. B., Sacher-Huvelin, S., Holst, J. J., Cuber, J. C., and Galmiche, J. P. (2003). Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease. Gastroenterology 124, 894-902. doi: 10.1053/gast.2003.50159
54. Poirier, P., Giles, T. D., Bray, G. A., Hong, Y., Stern, J. S., Pi-Sunyer, F. X., et al. (2006). Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition Physical Activity, and Metabolism. Circulation 113, 898-918. doi: 10.1161/CIRCULATIONAHA.106.171016
55. Prawitt, J., Caron, S., and Staels, B. (2011). Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr. Diab. Rep. 11, 160-166. doi: 10.1007/s11892-011-0187-x
56. Psychogios, N., Hau, D. D., Peng, J., Guo, A. C., Mandal, R., Bouatra, S., et al. (2011). The human serum metabolome. PLoS ONE 6:e16957. doi: 10.1371/journal.pone.0016957
57. Qin, J., Li, Y., Cai, Z., Li, S. S., Zhu, J., Zhang, F., et al. (2012). A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55-60. doi: 10.1038/nature11450
58. Ridlon, J. M., Kang, D.-J., and Hylemon, P. B. (2006). Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241-259. doi: 10.1194/jlr.R500013-JLR200
59. Romano, K. A., Vivas, E. I., Amador-Noguez, D., and Rey, F. E. (2015). Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide. MBio 6:e02481. doi: 10.1128/mBio.02481-14
60. Salek, R. M., Maguire, M. L., Bentley, E., Rubtsov, D. V., Hough, T., Cheeseman, M., et al. (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
61. Samuel, B. S., Shaito, A., Motoike, T., Rey, F. E., Backhed, F., Manchester, J. K., et al. (2008). Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. U.S.A. 105, 16767-16772. doi: 10.1073/pnas.0808567105
62. Sanz, Y., Rastmanesh, R., Agostoni, C., and Agostonic, C. (2013). Understanding the role of gut microbes and probiotics in obesity: how far are we? Pharmacol. Res. 69, 144-155. doi: 10.1016/j.phrs.2012.10.021
63. Scalbert, A., Brennan, L., Fiehn, O., Hankemeier, T., Kristal, B. S., van Ommen, B., et al. (2009). Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research. Metabolomics 5, 435-458. doi: 10.1007/s11306-009-0168-0
64. Schwiertz, A., Taras, D., Schäfer, K., Beijer, S., Bos, N. A., Donus, C., et al. (2010). Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18, 190-195. doi: 10.1038/oby.2009.167
65. Shen, J., Obin, M. S., and Zhao, L. (2013). The gut microbiota, obesity and insulin resistance. Mol. Aspects Med. 34, 39-58. doi: 10.1016/j.mam.2012.11.001
66. Shoaie, S., Ghaffari, P., Kovatcheva-Datchary, P., Mardinoglu, A., Sen, P., Pujos-Guillot, E., et al. (2015). Quantifying diet-induced metabolic changes of the human gut microbiome. Cell Metab. 22, 320-331. doi: 10.1016/j.cmet.2015.07.001
67. Suhre, K., Meisinger, C., Döring, A., Altmaier, E., Belcredi, P., Gieger, C., et al. (2010). Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting. PLoS ONE 5:e13953. doi: 10.1371/journal.pone.0013953
68. Sun, L., Yu, Z., Ye, X., Zou, S., Li, H., Yu, D., et al. (2010). A marker of endotoxemia is associated with obesity and related metabolic disorders in apparently healthy Chinese. Diabetes Care 33, 1925-1932. doi: 10.2337/dc10-0340
69. Swann, J. R., Want, E. J., Geier, F. M., Spagou, K., Wilson, I. D., Sidaway, J. E., et al. (2011). Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc. Natl. Acad. Sci. U.S.A. 108(Suppl.), 4523-4530. doi: 10.1073/pnas.1006734107
70. Thomas, C., Gioiello, A., Noriega, L., Strehle, A., Oury, J., Rizzo, G., et al. (2009). TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167-177. doi: 10.1016/j.cmet.2009.08.001
71. Thomas, C., Pellicciari, R., Pruzanski, M., Auwerx, J., and Schoonjans, K. (2008). Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov. 7, 678-693. doi: 10.1038/nrd2619
72. Tilg, H., Moschen, A. R., and Kaser, A. (2009). Obesity and the microbiota. Gastroenterology 136, 1476-1483. doi: 10.1053/j.gastro.2009.03.030
73. Tremaroli, V., and Bäckhed, F. (2012). Functional interactions between the gut microbiota and host metabolism. Nature 489, 242-249. doi: 10.1038/nature11552
74. Turnbaugh, P. J., and Gordon, J. I. (2009). The core gut microbiome, energy balance and obesity. J. Physiol. 587, 4153-4158. doi: 10.1113/jphysiol.2009.174136
75. Venema, K. (2010). Role of gut microbiota in the control of energy and carbohydrate metabolism. Curr. Opin. Clin. Nutr. Metab. Care 13, 432-438. doi: 10.1097/MCO.0b013e32833a8b60
76. Vrieze, A., Holleman, F., Zoetendal, E. G., de Vos, W. M., Hoekstra, J. B. L., and Nieuwdorp, M. (2010). The environment within: how gut microbiota may influence metabolism and body composition. Diabetologia 53, 606-613. doi: 10.1007/s00125-010-1662-7
77. Vrieze, A., Out, C., Fuentes, S., Jonker, L., Reuling, I., Kootte, R. S., et al. (2014). Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J. Hepatol. 60, 824-831. doi: 10.1016/j.jhep.2013.11.034
78. Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., Dugar, B., et al. (2011). Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57-63. doi: 10.1038/nature09922
79. Warrier, M., Shih, D. M., Burrows, A. C., Ferguson, D., Gromovsky, A. D., Brown, A. L., et al. (2015). The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. doi: 10.1016/j.celrep.2014.12.036 [Epub ahead of print].,
80. Watanabe, M., Houten, S. M., Mataki, C., Christoffolete, M. A., Kim, B. W., Sato, H., et al. (2006). Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439, 484-489. doi: 10.1038/nature04330
81. Wei, L., Liao, P., Wu, H., Li, X., Pei, F., Li, W., et al. (2008). Toxicological effects of cinnabar in rats by NMR-based metabolic profiling of urine and serum. Toxicol. Appl. Pharmacol. 227, 417-429. doi: 10.1016/j.taap.2007.11.015
82. Won, E.-Y., Yoon, M.-K., Kim, S.-W., Jung, Y., Bae, H.-W., Lee, D., et al. (2013). Gender-specific metabolomic profiling of obesity in leptin-deficient ob/ob mice by 1H NMR spectroscopy. PLoS ONE 8:e75998. doi: 10.1371/journal.pone.0075998
83. World Health Organization [WHO] (2013). Obesidad y Sobrepeso, 311. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/[Accessed April 2, 2014].
84. Zeisel, S. H. (2000). Choline: an essential nutrient for humans. Nutrition 16, 669-671. doi: 10.1016/S0899-9007(00)00349-X
85. Zhang, X., Wang, Y., Hao, F., Zhou, X., Han, X., Tang, H., et al. (2009). Human serum metabonomic analysis reveals progression axes for glucose intolerance and insulin resistance statuses. J. Proteome Res. 8, 5188-5195. doi: 10.1021/pr900524z
86. Zhao, X., Fritsche, J., Wang, J., Chen, J., Rittig, K., Schmitt-Kopplin, P., et al. (2010). Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits. Metabolomics 6, 362-374. doi: 10.1007/s11306-010-0203-1