Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Epidemiology and Population Health

Effectiveness of vitamin D therapy in improving metabolomic biomarkers in obesity phenotypes: Two randomized clinical trials

Subjects

Abstract

Background

Uncertainty remains about the effect of vitamin D therapy on biomarkers of health status in obesity. The molecular basis underlying this controversy is largely unknown.

Objective

To address the existing gap, our study sought to compare changes in metabolomic profiles of obesity phenotypes (metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO)) patients with sub-optimal levels of vitamin D following vitamin D supplementation.

Methods

We conducted two randomized double-blind clinical trials on participants with either of the two obesity phenotypes from Tehran province. These phenotypes were determined by the Adult Treatment Panel-III criteria. Patients in each of the MHO (n = 110) and MUHO (n = 105) groups were separately assigned to receive either vitamin D (4000 IU/d) or placebo for 4 months. Pre- and post-supplementation plasma metabolomic profiling were performed using Liquid chromatography coupled to a triple quadrupole mass spectrometry. Multivariable linear regression was used to explore the association of change in each metabolite with the trial assignment (vitamin D/placebo) across obesity phenotypes.

Results

Metabolites (n = 104) were profiled in 82 MHO and 78 MUHO patients. After correction for multiple comparisons, acyl-lysophosphatidylcholines C16:0, C18:0, and C18:1, diacyl-phosphatidylcholines C32:0, C34:1, C38:3, and C38:4, and sphingomyelin C40:4 changed significantly in response to vitamin D supplementation only in MUHO phenotype. The interaction analysis revealed that vitamin D therapy was different between the two obesity phenotypes based on acyl-lysophosphatidylcholines C16:0 and C16:1 and citrulline which were altered significantly after supplementation. Changes in metabolites were associated with changes in cardiometabolic biomarkers after the intervention.

Conclusions

Vitamin D treatment influenced the obesity-related plasma metabolites only in adults with obesity and metabolically unhealthy phenotype. Therefore, not all patients with obesity may benefit from an identical strategy for vitamin D therapy. These findings provide mechanistic basis highlighting the potential of precision medicine to mitigate diseases in health-care settings.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Adams KF, Schatzkin A, Leitzmann Harris TB, Kipnis V, Mouw T, Ballard-Barbash R, et al. Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old. N Engl J Med. 2006;355:763–78.

    Article  CAS  Google Scholar 

  2. Di Angelantonio E, Bhupathiraju SN, Wormser D, Gao P, Kaptoge S, de Gonzalez AB, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;388:776–86.

    Article  Google Scholar 

  3. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world—a growing challenge. N Engl J Med. 2007;356:213–5.

    Article  CAS  Google Scholar 

  4. Phillips CatherineM. Metabolically healthy obesity: definitions, determinants and clinical implications. Rev Endocr Metab Disord. 2013;14:219–27.

    Article  CAS  Google Scholar 

  5. Primeau V, Coderre L, Karelis A, Brochu M, Lavoie M, Messier V. Characterizing the profile of obese patients who are metabolically healthy. Int J Obes. 2011;35:971–81.

    Article  CAS  Google Scholar 

  6. Bell JA, Kivimaki M, Hamer M. Metabolically healthy obesity and risk of incident type 2 diabetes: a meta‐analysis of prospective cohort studies. Obes Rev. 2014;15:504–15.

    Article  CAS  Google Scholar 

  7. Hinnouho GM, Czernichow S, Dugravot A, Batty GD, Kivimaki M, Singh-Manoux A. Metabolically healthy obesity and risk of mortality does the definition of metabolic health matter? Diabetes Care. 2013;36:2294–300.

    Article  CAS  Google Scholar 

  8. Karelis AD, Rabasa-Lhoret R. Inclusion of C-reactive protein in the identification of metabolically healthy but obese (MHO) individuals. Diabetes Metab. 2008;34:183–4.

    Article  CAS  Google Scholar 

  9. Phillips CM, Dillon C, Harrington JM, McCarthy VJC, Kearney PM, Fitzgerald AP, et al. Defining metabolically healthy obesity: role of dietary and lifestyle factors. PLoS ONE. 2013;8:e76188.

    Article  CAS  Google Scholar 

  10. Karelis AD, Messier V, Brochu M, Rabasa-Lhoret R. Metabolically healthy but obese women: effect of an energy-restricted diet. Diabetologia. 2008;51:1752–4.

    Article  CAS  Google Scholar 

  11. Shin MJ, Hyun YJ, Kim OY, Kim JY, Jang Y, Lee JH. Weight loss effect on inflammation and LDL oxidation in metabolically healthy but obese (MHO) individuals: low inflammation and LDL oxidation in MHO women. Int J Obes. 2006;30:1529–34.

    Article  CAS  Google Scholar 

  12. Holick MF. Vitamin D Deficiency. N Engl J Med. 2007;357:266–81.

    Article  CAS  Google Scholar 

  13. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18–28.

    Article  CAS  Google Scholar 

  14. Yeum K-J, Song BC, Joo N-S. Impact of geographic location on vitamin D status and bone mineral density. Int J Environ Res Public Health. 2016;13:184.

    Article  Google Scholar 

  15. Strange RC, Shipman KE, Ramachandran S. Metabolic syndrome: a review of the role of vitamin D in mediating susceptibility and outcome. World J Diabetes. 2015;6:896–911.

    Article  Google Scholar 

  16. Fung GJ, Steffen LM, Zhou X, Harnack L, Tang W, Lutsey PL, et al. Vitamin D intake is inversely related to risk of developing metabolic syndrome in African American and white men and women over 20 y: the Coronary Artery Risk Development in Young Adults study. Am J Clin Nutr. 2012;96:24–9.

    Article  CAS  Google Scholar 

  17. Belenchia AM, Tosh AK, Hillman LS, Peterson CA. Correcting vitamin D insufficiency improves insulin sensitivity in obese adolescents: a randomized controlled trial. Am J Clin Nutr. 2013;97:774–81.

    Article  CAS  Google Scholar 

  18. Jamka M, Woźniewicz M, Jeszka J, Mardas M, Bogdański P, Stelmach-Mardas M. The effect of vitamin D supplementation on insulin and glucose metabolism in overweight and obese individuals: systematic review with meta-analysis. Sci Rep. 2015;5:16142.

    Article  CAS  Google Scholar 

  19. Mousa A, Naderpoor N, de Courten MPJ, Teede H, Kellow N, Walker K, et al. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D–deficient, overweight or obese adults: a randomized placebo-controlled trial. Am J Clin Nutr. 2017;105:1372–81.

    CAS  PubMed  Google Scholar 

  20. vinh quốc Lương K, Nguyễn LTH. The beneficial role of vitamin D in obesity: possible genetic and cell signaling mechanisms. Nutr J. 2013;12:89.

    Article  Google Scholar 

  21. Zhou JC, Zhu YM, Guo P, Chen Z, Xie FZ, Liu XL, et al. Serum 25(OH)D and lipid levels in Chinese obese and normal weight males before and after oral vitamin D supplementation. Biomed Environ Sci. 2013;26:801–7.

    CAS  PubMed  Google Scholar 

  22. Wang H, Xia N, Yang Y, Peng D-Q. Influence of vitamin D supplementation on plasma lipid profiles: a meta-analysis of randomized controlled trials. Lipids Health Dis. 2012;11:42.

    Article  CAS  Google Scholar 

  23. Stokes CS, Lammert F. Vitamin D supplementation: less controversy, more guidance needed. F1000Res. 2016;5:F1000. Faculty Rev-2017.

    Article  Google Scholar 

  24. Schöttker B, Brenner H. Vitamin D as a resilience factor, helpful for survival of potentially fatal conditions: a hypothesis emerging from recent findings of the ESTHER Cohort Study and the CHANCES Consortium. Nutrients. 2015;7:3264–78.

    Article  Google Scholar 

  25. Rankin NJ, Preiss D, Welsh P, Sattar N. Applying metabolomics to cardiometabolic intervention studies and trials: past experiences and a roadmap for the future. Int J Epidemiol. 2016;45:1351–71.

    Article  Google Scholar 

  26. 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;62:961–9.

    Article  CAS  Google Scholar 

  27. Kim H-J, Kim JH, Noh S, Hur HJ, Sung MJ, Hwang J-T, et al. Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J Proteome Res. 2010;10:722–31.

    Article  Google Scholar 

  28. Wiklund PK, Pekkala S, Autio R, Munukka E, Xu L, Saltevo J. Serum metabolic profiles in overweight and obese women with and without metabolic syndrome. Diabetol Metab Syndr. 2014;6:40.

    Article  Google Scholar 

  29. Hu FB, Narasimhan K. Nutritional genomics and metabolomics in obesity and type 2 diabetes. BMC Genomics. 2014;15 Suppl 2:O10.

    Article  Google Scholar 

  30. Turner N. New insight into obesity and metabolic disease through metabolite profiling. J Metabonomics Metabolites. 2012;1:1.

    Article  Google Scholar 

  31. Rutkowsky JM, Knotts TA, Ono-Moore KD, McCoin CS, Huang S, Schneider D, et al. Acylcarnitines activate proinflammatory signaling pathways. Am J Physiol Endocrinol Metab. 2014;306:E1378–87.

    Article  CAS  Google Scholar 

  32. Zhang A, Sun H, Wang X. Power of metabolomics in biomarker discovery and mining mechanisms of obesity. Obes Rev. 2013;14:344–9.

    Article  CAS  Google Scholar 

  33. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. 2007;85:6–18.

    Article  CAS  Google Scholar 

  34. World Health Organization. Obesity: preventing and managing the global epidemic. World Health Organization; 2000. http://www.who.int/nutrition/publications/obesity/WHO_TRS_894/en.

  35. Expert Panel on D, Evaluation, and Treatment of High Blood Cholesterol in A. Executive summary of the third report of the national cholesterol education program (ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii). JAMA. 2001;285:2486–97.

    Article  Google Scholar 

  36. Cleeman JI, Grundy SM, Becker D, Clark LT. Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III). JAMA. 2001;285:2486–97.

    Article  Google Scholar 

  37. Booth ML, Pratt M, Ekelund U, Yngve A, Sallis JF, Oja P. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35(8):1381–95.

    Google Scholar 

  38. Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. 2005;90:3215–24.

    Article  CAS  Google Scholar 

  39. Lindsay KL, Hellmuth C, Uhl O, Buss C, Wadhwa PD, Koletzko B, et al. Longitudinal metabolomic profiling of amino acids and lipids across healthy pregnancy. PLoS ONE. 2015;10:e0145794.

    Article  Google Scholar 

  40. Harder U, Koletzko B, Peissner W. Quantification of 22 plasma amino acids combining derivatization and ion-pair LC-MS/MS. J Chromatogr B. 2011;879:495–504.

    Article  CAS  Google Scholar 

  41. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28:882–3.

    Article  CAS  Google Scholar 

  42. Laferrère B,Reilly D,Arias S,Swerdlow N,Gorroochurn P,Bawa B, et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med. 2011;3:80re2.

    Article  Google Scholar 

  43. Brock K, Huang WY, Fraser DR, Ke L, Tseng M, Stolzenberg-Solomon R, Peters U, et al. Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women. J Steroid Biochem Mol Biol. 2010;121:462–6.

    Article  CAS  Google Scholar 

  44. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98:451–9.

    Article  CAS  Google Scholar 

  45. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Ser B Stat Methodol. 1995;57:289–300.

    Google Scholar 

  46. Stefan N, Haring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1:152–62.

    Article  Google Scholar 

  47. Xiao Q, Moore SC, Keadle SK, Xiang Y-B, Zheng W, Peters TM, et al. Objectively measured physical activity and plasma metabolomics in the Shanghai Physical Activity Study. Int J Epidemiol. 2016;45:1433–44.

    Article  Google Scholar 

  48. O’Sullivan A, Gibney MJ, Brennan L. Dietary intake patterns are reflected in metabolomic profiles: potential role in dietary assessment studies. Am J Clin Nutr. 2011;93:314–21.

    Article  Google Scholar 

  49. Kahan BC, Jairath V, Doré CJ, Morris TP. The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. Trials. 2014;15:139.

    Article  Google Scholar 

  50. Fitzmaurice GM, Laird NM, Ware JH. Applied longitudinal analysis. 2nd ed. The United States of America: Wiley Series in Probability and Statistics, John Wiley and Sons; 2011. p. 132.

  51. Esmen SE, Yılmaz S, Kebapcılar L, Ünlü A, İpekci SH, Abusoglu S. Effects of vitamin D replacement on the disease activity and inflammatory parameters such as IL-1, IL-6, TNF-α, asymmetric dimethylarginine (ADMA) and arginine/adma ratio in ankylosing spondylitis. Ann Rheum Dis. 2017;76:931.

    Google Scholar 

  52. Jordea R, Grimnes G. Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids. Prog Lipid Res. 2011;50:303–12.

    Article  Google Scholar 

  53. Stepien M, Nugent AP, Brennan L. Metabolic profiling of human peripheral blood mononuclear cells: Influence of vitamin d status and gender. Metabolites. 2014;4:248–59.

    Article  Google Scholar 

  54. Reinehr T, Wolters B, Knop C, Lass N, Hellmuth C, Harder U, et al. Changes in the serum metabolite profile in obese children with weight loss. Eur J Nutr. 2014;54:173–81.

    Article  Google Scholar 

  55. Dubé JJ, Amati F, Stefanovic-Racic M, Toledo FGS, Sauers SE, Goodpaster BH. Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited. Am J Physiol Endocrinol Metab. 2008;294:E882–E8.

    Article  Google Scholar 

  56. Meikle PJ, Summers SA. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol. 2017;13:79–91.

    Article  CAS  Google Scholar 

  57. Li Z, Agellon LB, Allen TM, Umeda M, Jewell L, Mason A, et al. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab. 2006;3:321–31.

    Article  CAS  Google Scholar 

  58. Martínez-Uña M, Varela-Rey M, Cano A, Fernández-Ares L, Beraza N, Aurrekoetxea I, Martínez-Arranz I, et al. Excess S-adenosylmethionine reroutes phosphatidylethanolamine towards phosphatidylcholine and triglyceride synthesis. Hepatology. 2013;58:1296–305.

    Article  Google Scholar 

  59. Sekas G, Patton GM, Lincoln EC, Robins SJ. Origin of plasma lysophosphatidylcholine: evidence for direct hepatic secretion in the rat. J Lab Clin Med. 1985;105:190–4.

    CAS  PubMed  Google Scholar 

  60. Song J, Costa KAD, Fischer LM, Kohlmeier M, Kwock L, Wang S, et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J. 2005;19:1266–71.

    Article  CAS  Google Scholar 

  61. Montecino M, Stein GS, Stein JL, Lian JB, van Wijnen AJ, Carvallo L, et al. Vitamin D control of gene expression: temporal and spatial parameters for organization of the regulatory machinery. Crit Rev Eukaryot Gene Expr. 2008;18:163–72.

    Article  CAS  Google Scholar 

  62. Tarroni P, Villa I, Mrak E, Zolezzi F, Mattioli M, Gattuso C, et al. Microarray analysis of 1,25(OH)2D3 regulated gene expression in human primary osteoblasts. J Cell Biochem. 2012;113:640–9.

    Article  CAS  Google Scholar 

  63. Klose RJ, Zhang Y. Regulation of histone methylation by demethylimination and demethylation. Nat Rev Mol Cell Biol. 2007;8:307–18.

    Article  CAS  Google Scholar 

  64. Braithwaite MC, Kumar P, Tyagi C, Tomar LK, Choonara YE, Pillay V. Vitamin D therapy and related metabolomics: is the calciferol dose and form the only requirements for successful clinical therapeutics? Med Hypotheses. 2013;81:656–63.

    Article  CAS  Google Scholar 

  65. Dutta D, Mondal SA, Choudhuri S, Maisnam I, Hasanoor Reza AH, Bhattacharya B, et al. Vitamin-D supplementation in prediabetes reduced progression to type 2 diabetes and was associated with decreased insulin resistance and systemic inflammation: an open label randomized prospective study from Eastern India. Diabetes Res Clin Pract. 2014;103:e18–23.

    Article  CAS  Google Scholar 

  66. Naharci I, Bozoglu E, Kocak N, Doganci S, Doruk H, Serdar M. Effect of vitamin D on insulin sensitivity in elderly patients with impaired fasting glucose. Geriatr Gerontol Int. 2012;12:454–60.

    Article  Google Scholar 

  67. Harinarayan C, Arvind S, Joshi S, Thennarasu K, Vedavyas V, Baindur A. Improvement in pancreatic β-cell function with vitamin D and calcium supplementation in vitamin D-deficient nondiabetic subjects. Endocr Pract. 2014;20:129–38.

    Article  Google Scholar 

  68. Nwosu BU, Maranda L. The effects of vitamin D supplementation on hepatic dysfunction, vitamin D status, and glycemic control in children and adolescents with vitamin D deficiency and either type 1 or type 2 diabetes mellitus. PLoS ONE. 2014;9:e99646.

    Article  Google Scholar 

  69. Al-Shoumer KAS, Al-Essa TM. Is there a relationship between vitamin D with insulin resistance and diabetes mellitus? World J Diabetes. 2015;6:1057–64.

    Article  Google Scholar 

Download references

Acknowledgements

This study was funded by Tehran University of Medical Sciences (28829-161-01-94, 1919-98-01-94). The funding partners were School of Nutritional Sciences and Dietetic of Tehran University of Medical Sciences and Non-Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute of Tehran University of Medical Sciences. We thank Dr. Stella Aslibekyan, Oana Zeleznik, Dr. Elizabeth M. Poole, and Dr. Peter Kraft who provided statistical advice, Dr. Hadi Tabibi, Dr. Ali Keshavarz, and the Department of social and cultural affairs of Tehran municipality that assisted with participant recruitment and Dr. Mohammad Hassan Javanbakht who assisted us to provide the study supplements.

Author contributions

MB, LQ, MSY, and AD designed the research; MB, FF, and ZE conducted the research; MB, FF, and AD provided the essential materials; BK and OU conducted the metabolomics measurements; MB and MSY performed the statistical analysis; MB wrote the paper; MB, FF, LQ, and AD had primary responsibility for final content. Trial registration: this study was registered at www.irct.ir as IRCT2015061522762N1.

Funding

Tehran University of Medical Sciences.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Lu Qi or Farshad Farzadfar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

41366_2018_107_MOESM1_ESM.doc

Multivariable linear regression analyses for the association* of vitamin D supplementation with changes in plasma amino acids† by obesity phenotypes

Differences* of anthropometric and metabolic variables after vitamin D supplementation by obesity phenotypes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bagheri, M., Djazayery, A., Qi, L. et al. Effectiveness of vitamin D therapy in improving metabolomic biomarkers in obesity phenotypes: Two randomized clinical trials. Int J Obes 42, 1782–1796 (2018). https://doi.org/10.1038/s41366-018-0107-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-018-0107-0

This article is cited by

Search

Quick links