The metabolome profiling of obese and non-obese individuals: Metabolically healthy obese and unhealthy non-obese paradox

Document Type: Original Article

Authors

1 Department of Chemistry, Sharif University of Technology, Tehran, Iran

2 Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran

3 Chemical Injuries Research Center, Systems Biology and Poisoning Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): The molecular basis of “metabolically healthy obese” and “metabolically unhealthy non-obese” phenotypes is not fully understood. Our objective was to identify metabolite patterns differing in obese (metabolically healthy vs unhealthy (MHO vs MUHO)) and non-obese (metabolically healthy vs unhealthy (MHNO vs MUHNO)) individuals.
Materials and Methods: This case-control study was performed on 86 subjects stratified into four groups using anthropometric and clinical measurements: MHO (21), MUHO (21), MHNO (22), and MUHNO (22). Serum metabolites were profiled using nuclear magnetic resonance (NMR). Multivariate analysis was applied to uncover discriminant metabolites, and enrichment analysis was performed to identify underlying pathways.
Results: Significantly higher levels of glutamine, asparagine, alanine, L-glutathione reduced, 2-aminobutyrate, taurine, betaine, and choline, and lower level of D-sphingosine were observed in MHO group compared with MUHO. In comparison of MHNO and MUHNO groups, significantly lower levels of alanine, glycine, glutamine, histidine, L-glutathione reduced, and betaine, and higher levels of isoleucine, L-proline, cholic acid, and carnitine appeared in MUHNO individuals. Moreover, significantly affected pathways included amino acid metabolism, urea cycle and ammonia recycling in MUHO subjects and glutathione metabolism, amino acid metabolism, and ammonia recycling in MUHNO members.
Conclusion: Literature review helped us to hint that altered levels of most metabolites might associate to insulin sensitivity and insulin resistance in MHO and MUHNO individuals, respectively. Besides, abnormal amino acid metabolism and ammonia recycling involved in unhealthy phenotypes (MUHO, MUHNO) might be associated with insulin resistance.

Keywords


1. Ogden CL, Carroll MD, Flegal KM. Epidemiologic trends in overweight and obesity. Endocrinol Metab Clin North Am 2003; 32:741-760.
2. Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab 2012; 97:2482-2488.
3. Appleton SL, Seaborn CJ, Visvanathan R, Hill CL, Gill TK, Taylor AW, et al. Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype: a cohort study. Diabetes care 2013; 36:2388-2394.
4. Phillips CM, Dillon C, Harrington JM, McCarthy VJ, Kearney PM, Fitzgerald AP, et al. Defining metabolically healthy obesity: role of dietary and lifestyle factors. PloS one 2013; 8:e76188.
5. Badoud F, Perreault M, Zulyniak MA, Mutch DM. Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals. FASEB J 2014; 29:748-758.
6. Kramer CK, Zinman B, Retnakaran R. Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann Intern Med 2013; 159:758-769.
7. Aguilar-Salinas CA, García EG, Robles L, Riano D, Ruiz-Gomez DG, García-Ulloa AC, et al. High adiponectin concentrations are associated with the metabolically healthy obese phenotype. J Clin Endocrinol Metab 2008; 93:4075-4079.
8. Karelis AD, Faraj M, Bastard J-P, St-Pierre DH, Brochu M, Prud’homme D, et al. The metabolically healthy but obese individual presents a favorable inflammation profile. J Clin Endocrinol Metab 2005; 90:4145-4150.
9. Brochu M, Tchernof A, Dionne IJ, Sites CK, Eltabbakh GH, Sims EA, et al. What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women? J Clin Endocrinol Metab 2001; 86:1020-1025.
10. Kwon B-J, Kim D-W, Her S-H, Kim D-B, Jang S-W, Cho E-J, et al. Metabolically obese status with normal weight is associated with both the prevalence and severity of angiographic coronary artery disease. Metabolism 2013; 62:952-960.
11. Stefan N, Schick F, Häring H-U. Causes, characteristics, and consequences of metabolically unhealthy normal weight in humans. Cell Metab 2017; 26:292-300.
12. Nobakht BF, Arefi Oskouie A, Rezaei-Tavirani M, Aliannejad R, Taheri S, Fathi F, et al. NMR spectroscopy-based metabolomic study of serum in sulfur mustard exposed patients with lung disease. Biomarkers 2017; 22:413-419.
13. Zhang A, Sun H, Wang X. Power of metabolomics in biomarker discovery and mining mechanisms of obesity. Obes Rev 2013; 14:344-349.
14. Lehmann R, Friedrich T, Krebiehl G, Sonntag D, Häring H-U, Fritsche A, et al. Metabolic profiles during an oral glucose tolerance test in pregnant women with and without gestational diabetes. Exp Clin Endocrinol Diabetes 2015; 123:483-438.
15. Chen H, Tseng Y, Wang S, Tsai Y, Chang C, Kuo T, et al. The metabolome profiling and pathway analysis in metabolic healthy and abnormal obesity. Int J Obes (Lond) 2015; 39:1241-1248.
16. Kalantari S, Nafar M, Samavat S, Parvin M, Nobakht M. GH BF, Barzi F. 1H NMR‐based metabolomics exploring urinary biomarkers correlated with proteinuria in focal segmental glomerulosclerosis: a pilot study. Magn Reson Chem 2016; 54:821-826.
17. Emwas A-H, Luchinat C, Turano P, Tenori L, Roy R, Salek RM, et al. Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a review. Metabolomics 2015; 11:872-894.
18. Badoud F, Lam KP, DiBattista A, Perreault M, Zulyniak MA, Cattrysse B, et al. Serum and adipose tissue amino acid homeostasis in the metabolically healthy obese. J Proteome Res 2014; 13:3455-3466.
19. Wiklund PK, Pekkala S, Autio R, Munukka E, Xu L, Saltevo J, et al. Serum metabolic profiles in overweight and obese women with and without metabolic syndrome. Diabetol Metab Syndr 2014; 6:40.
20. Phillips CM. Metabolically healthy obesity: definitions, determinants and clinical implications. Rev Endocr Metab Disord 2013; 14:219-227.
21. Brown FF, Campbell ID, Kuchel PW. Human erythrocyte metabolism studies by 1H spin echo NMR. FEBS Lett 1977; 82:12-16.
22. Viant MR. Improved methods for the acquisition and interpretation of NMR metabolomic data. Biochem Biophys Res Commun 2003; 310:943-948.
23. Ordovás Muñoz JM. Predictores de obesidad: el” poder” de las omicas. Nutr Hosp 2013; 28:63-72.
24. Dimski DS. Ammonia metabolism and the urea cycle: function and clinical implications. J Vet Intern Med 1994; 8:73-78.
25. Cheng S, Rhee EP, Larson MG, Lewis GD, McCabe EL, Shen D, et al. Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 2012;125:2222–2231.
26. Guevara-Cruz M, Vargas-Morales J, Méndez-García A, López-Barradas A, Granados-Portillo O, Ordaz-Nava G, et al. Amino acid profiles of young adults differ by sex, body mass index and insulin resistance. Nutr Metab Cardiovasc Dis 2018;28:393-401.
27. Brennan L, Shine A, Hewage C, Malthouse JPG, Brindle KM, McClenaghan N, et al. A nuclear magnetic resonance-based demonstration of substantial oxidative l-alanine metabolism and l-alanine-enhanced glucose metabolism in a clonal pancreatic β-cell line: metabolism of l-alanine is important to the regulation of insulin secretion. Diabetes 2002; 51:1714-1721.
28. Biolo G, Antonione R, De Cicco M. Glutathione metabolism in sepsis. Crit Care Med 2007; 35:S591-S595.
29. Irino Y, Toh R, Nagao M, Mori T, Honjo T, Shinohara M, et al. 2-Aminobutyric acid modulates glutathione homeostasis in the myocardium. Sci Rep 2016; 6:36749.
30. Murakami S. Role of taurine in the pathogenesis of obesity. Mol Nutr Food Res 2015; 59:1353-1363.
31. Gao X, Wang Y, Sun G. High dietary choline and betaine intake is associated with low insulin resistance in the Newfoundland population. Nutrition 2017; 33:28-34.
32. Wang Z, Yao T, Pini M, Zhou Z, Fantuzzi G, Song Z. Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2010; 298:G634-G642.
33. Donner TW, Magder LS, Zarbalian K. Dietary supplementation with d-tagatose in subjects with type 2 diabetes leads to weight loss and raises high-density lipoprotein cholesterol. Nutr Res 2010; 30:801-806.
34. Lu Y, Levin G, Donner T. Tagatose, a new antidiabetic and obesity control drug. Diabetes Obes Metab 2008; 10:109-134.
35. Candi E, Tesauro M, Cardillo C, Lena AM, Schinzari F, Rodia G, et al. Metabolic profiling of visceral adipose tissue from obese subjects with or without metabolic syndrome. Biochem J 2018;475: 1019-1035.
36. Lopategi A, López-Vicario C, Alcaraz-Quiles J, García-Alonso V, Rius B, Titos E, et al. Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction. Mol Cell Endocrinol 2016; 419:44-59.
37. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 2015; 6:456-480.
38. Roberge JN, Brubaker PL. Regulation of intestinal proglucagon-derived peptide secretion by glucose-dependent insulinotropic peptide in a novel enteroendocrine loop. Endocrinology 1993; 133:233-240.
39. Perseghin G, Ghosh S, Gerow K, Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 1997; 46:1001-1009.
40. Batch BC, Shah SH, Newgard CB, Turer CB, Haynes C, Bain JR, et al. Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness. Metabolism 2013; 62:961-969.
41. Cariou B, Chetiveaux M, Zaïr Y, Pouteau E, Disse E, Guyomarc’h-Delasalle B, et al. Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults. Nutr Metab (Lond) 2011; 8:48.
42. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7:45-56.
43. Aung K, Lorenzo C, Hinojosa MA, Haffner SM. Risk of developing diabetes and cardiovascular disease in metabolically unhealthy normal-weight and metabolically healthy obese individuals. J Clin Endocrinol Metab 2014; 99:462-468.