Article | Published:

Molecular Biology

Dietary weight loss intervention improves subclinical atherosclerosis and oxidative stress markers in leukocytes of obese humans

International Journal of Obesity (2019) | Download Citation

Abstract

Background

The relationship between caloric restriction-mediated weight loss and the generation of ROS and its effects on atherosclerotic markers in obesity is not fully understood. Therefore, we set out to investigate whether dietary weight loss intervention improves markers of oxidative stress in leukocytes and subclinical parameters of atherosclerosis.

Subjects and Methods

This was an interventional study of 59 obese subjects (BMI > 35 kg/m2) who underwent 6 months of dietary therapy, including a 6-week very-low-calorie diet (VLCD) followed by an 18-week low-calorie diet (LCD). We determined clinical parameters, inflammatory markers—hsCRP, TNFα and NFκB –, oxidative stress parameters—total superoxide, glutathione, catalase activity and protein carbonyl groups–, soluble cellular adhesion molecules—sICAM, sP-selectin, sPSGL-1 –, myeloperoxidase (MPO), leukocyte-endothelium cell interactions—rolling flux, velocity and adhesion—and LDL subfractions, before and after the dietary intervention.

Results

After losing weight, an improvement was observed in the patients’ anthropometric, blood pressure and metabolic parameters, and was associated with reduced inflammatory response (hsCRP, TNFα and NFκB). Oxidative stress parameters improved, since superoxide production and protein carbonyl content were reduced and antioxidant systems were enhanced. In addition, a significant reduction of subclinical markers of atherosclerosis—small and dense LDL particles, MPO, sP-selectin and leukocyte adhesion—and an increase in soluble PSGL-1 were reported.

Conclusions

Our findings reveal that the improvement of subclinical atherosclerotic markers after dietary weight loss intervention is associated with a reduction of oxidative stress in leukocytes and inflammatory pathways, suggesting that these are the underlying mechanisms responsible for the reduced risk of cardiovascular disease in obese subjects after losing weight.

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References

  1. 1.

    Fruhbeck G. Obesity: screening for the evident in obesity. Nat Rev Endocrinol. 2012;8:570–2.

  2. 2.

    Yin X, Lanza IR, Swain JM, Sarr MG, Nair KS, Jensen MD. Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size. J Clin Endocrinol Metab. 2014;99:E209–16.

  3. 3.

    Chattopadhyay M, Khemka VK, Chatterjee G, Ganguly A, Mukhopadhyay S, Chakrabarti S. Enhanced ROS production and oxidative damage in subcutaneous white adipose tissue mitochondria in obese and type 2 diabetes subjects. Mol Cell Biochem. 2015;399:95–103.

  4. 4.

    Lopez-Domenech S, Bañuls C, Diaz-Morales N, Escribano-Lopez I, Morillas C, Veses S, et al. Obesity impairs leukocyte-endothelium cell interactions and oxidative stress in humans. Eur J Clin Invest. 2018;48:e12985.

  5. 5.

    Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

  6. 6.

    Yang X, Li Y, Li Y, Ren X, Zhang X, Hu D, et al. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol. 2017;8:600.

  7. 7.

    Zernecke A, Weber C. Inflammatory mediators in atherosclerotic vascular disease. Basic Res Cardiol. 2005;100:93–101.

  8. 8.

    Golias C, Tsoutsi E, Matziridis A, Makridis P, Batistatou A, Charalabopoulos K. Review. Leukocyte and endothelial cell adhesion molecules in inflammation focusing on inflammatory heart disease. Vivo. 2007;21:757–69.

  9. 9.

    Zheng L, Nukuna B, Brennan ML, Sun M, Goormastic M, Settle M, et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest. 2004;114:529–41.

  10. 10.

    Vita JA, Brennan ML, Gokce N, Mann SA, Goormastic M, Shishehbor MH, et al. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation. 2004;110:1134–9.

  11. 11.

    Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2005;25:1102–11.

  12. 12.

    Victor VM, Rocha M, Banuls C, Sanchez-Serrano M, Sola E, Gomez M, et al. Mitochondrial complex I impairment in leukocytes from polycystic ovary syndrome patients with insulin resistance. J Clin Endocrinol Metab. 2009;94:3505–12.

  13. 13.

    Victor VM, Rocha M, Banuls C, Alvarez A, de Pablo C, Sanchez-Serrano M, et al. Induction of oxidative stress and human leukocyte/endothelial cell interactions in polycystic ovary syndrome patients with insulin resistance. J Clin Endocrinol Metab. 2011;96:3115–22.

  14. 14.

    Hernandez-Mijares A, Rocha M, Apostolova N, Borras C, Jover A, Banuls C, et al. Mitochondrial complex I impairment in leukocytes from type 2 diabetic patients. Free Radic Biol Med. 2011;50:1215–21.

  15. 15.

    Hernandez-Mijares A, Rocha M, Rovira-Llopis S, Banuls C, Bellod L, de Pablo C, et al. Human leukocyte/endothelial cell interactions and mitochondrial dysfunction in type 2 diabetic patients and their association with silent myocardial ischemia. Diabetes Care. 2013;36:1695–702.

  16. 16.

    Wood PD, Stefanick ML, Dreon DM, Frey-Hewitt B, Garay SC, Williams PT, et al. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med. 1988;319:1173–9.

  17. 17.

    Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, Smith West D, et al. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med. 2001;134:1–11.

  18. 18.

    Wycherley TP, Moran LJ, Clifton PM, Noakes M, Brinkworth GD. Effects of energy-restricted high-protein, low-fat compared with standard-protein, low-fat diets: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2012;96:1281–98.

  19. 19.

    Packard CJ. Small dense low-density lipoprotein and its role as an independent predictor of cardiovascular disease. Curr Opin Lipidol. 2006;17:412–7.

  20. 20.

    Koba S, Yokota Y, Hirano T, Ito Y, Ban Y, Tsunoda F, et al. Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis. J Atheroscler Thromb. 2008;15:250–60.

  21. 21.

    Lawler PR, Akinkuolie AO, Chu AY, Shah SH, Kraus WE, Craig D, et al. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc. 2017;6. https://doi.org/10.1161/JAHA.117.005549.

  22. 22.

    Sola E, Jover A, Lopez-Ruiz A, Jarabo M, Vaya A, Morillas C, et al. Parameters of inflammation in morbid obesity: lack of effect of moderate weight loss. Obes Surg. 2009;19:571–6.

  23. 23.

    Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110:1564–71.

  24. 24.

    Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Valenti V, Moncada R. et al. Peripheral mononuclear blood cells contribute to the obesity-associated inflammatory state independently of glycemic status: involvement of the novel proinflammatory adipokines chemerin, chitinase-3-like protein 1, lipocalin-2 and osteopontin. Genes Nutr. 2015;10:460–015-0460-8.

  25. 25.

    de Mello VD, Kolehmainen M, Pulkkinen L, Schwab U, Mager U, Laaksonen DE, et al. Downregulation of genes involved in NFkappaB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study. Diabetologia. 2008;51:2060–7.

  26. 26.

    Walther G, Obert P, Dutheil F, Chapier R, Lesourd B, Naughton G, et al. Metabolic syndrome individuals with and without type 2 diabetes mellitus present generalized vascular dysfunction: cross-sectional study. Arterioscler Thromb Vasc Biol. 2015;35:1022–9.

  27. 27.

    La Favor JD, Dubis GS, Yan H, White JD, Nelson MA, Anderson EJ, et al. Microvascular endothelial dysfunction in sedentary, obese humans is mediated by NADPH oxidase: influence of exercise training. Arterioscler Thromb Vasc Biol. 2016;36:2412–20.

  28. 28.

    Wiernsperger N, Rapin JR. Microvascular diseases: is a new era coming? Cardiovasc Hematol Agents Med Chem. 2012;10:167–83.

  29. 29.

    Dandona P, Mohanty P, Ghanim H, Aljada A, Browne R, Hamouda W, et al. The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation. J Clin Endocrinol Metab. 2001;86:355–62.

  30. 30.

    Frey RS, Ushio-Fukai M, Malik AB. NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. Antioxid Redox Signal. 2009;11:791–810.

  31. 31.

    Weseler AR, Bast A. Oxidative stress and vascular function: implications for pharmacologic treatments. Curr Hypertens Rep. 2010;12:154–61.

  32. 32.

    Davenpeck KL, Brummet ME, Hudson SA, Mayer RJ, Bochner BS. Activation of human leukocytes reduces surface P-selectin glycoprotein ligand-1 (PSGL-1, CD162) and adhesion to P-selectin in vitro. J Immunol. 2000;165:2764–72.

  33. 33.

    Yan S, Zhang X, Zheng H, Hu D, Zhang Y, Guan Q, et al. Clematichinenoside inhibits VCAM-1 and ICAM-1 expression in TNF-alpha-treated endothelial cells via NADPH oxidase-dependent IkappaB kinase/NF-kappaB pathway. Free Radic Biol Med. 2015;78:190–201.

  34. 34.

    Rios-Navarro C, de Pablo C, Collado-Diaz V, Orden S, Blas-Garcia A, Martinez-Cuesta MA, et al. Differential effects of anti-TNF-alpha and anti-IL-12/23 agents on human leukocyte-endothelial cell interactions. Eur J Pharmacol. 2015;765:355–65.

  35. 35.

    Woollard KJ, Suhartoyo A, Harris EE, Eisenhardt SU, Jackson SP, Peter K, et al. Pathophysiological levels of soluble P-selectin mediate adhesion of leukocytes to the endothelium through Mac-1 activation. Circ Res. 2008;103:1128–38.

  36. 36.

    Carr AC, Myzak MC, Stocker R, McCall MR, Frei B. Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis. FEBS Lett. 2000;487:176–80.

  37. 37.

    Delporte C, Van Antwerpen P, Vanhamme L, Roumeguere T, Zouaoui Boudjeltia K. Low-density lipoprotein modified by myeloperoxidase in inflammatory pathways and clinical studies. Mediat Inflamm. 2013;2013:971579.

  38. 38.

    Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003;108:1440–5.

  39. 39.

    Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003;349:1595–604.

  40. 40.

    Meuwese MC, Stroes ES, Hazen SL, van Miert JN, Kuivenhoven JA, Schaub RG, et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;50:159–65.

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Acknowledgements

We acknowledge the editorial assistance of Brian Normanly (CIBERehd). This study was supported by grant PI16/00301 and PI16/01083 from Carlos III Health Institute and has been co-funded by the European Regional Development Fund (ERDF “A way to build Europe”) and UGP-15–220 from FISABIO. Unrestricted grant from Menarini S.A. MM-H is a predoctoral fellowship from Valencian Regional Ministry of Education (ACIF/2015/226), SL-D, ND-M and ZA-J are recipients of a predoctoral fellowship and from Carlos III Health Institute (FI14/00350, FI14/00125 and FI17/00144, respectively). IE-L has a predoctoral fellowship from FISABIO (UGP-15–144). MR is recipient of Miguel Servet (CPII16/0037) contract from Carlos III Health Institute.

Author contribution

The authors’ responsibilities were as follows. MR and VM-V contributed to the conception and design of the study. CB assisted in the design of the experiments and provided support throughout the course of the study. CM, SL-D and MM-H carried out the recruitment, diagnosis and follow-up of the patients in the study. SL-D, MM-H, ZA-J, IE-L and ND-M performed the laboratory analyses and collected data. SL-D, MM-H and MR analyzed the data, performed the statistical analysis and drafted the manuscript. MR, and VM-V critically revised the manuscript and were responsible for its final content. All authors read and approved the final version of the manuscript.

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Author notes

  1. These authors contributed equally: Sandra López-Domènech, Mayte Martínez-Herrera

Affiliations

  1. Service of Endocrinology and Nutrition, University Hospital Doctor Peset-FISABIO, Av. Gaspar Aguilar 90, 46017, Valencia, Spain

    • Sandra López-Domènech
    • , Zaida Abad-Jiménez
    • , Carlos Morillas
    • , Irene Escribano-López
    • , Noelia Díaz-Morales
    • , Celia Bañuls
    • , Víctor M. Víctor
    •  & Milagros Rocha
  2. Service of Stomatology, University Hospital Doctor Peset-FISABIO, Av. Gaspar Aguilar 90, 46017, Valencia, Spain

    • Mayte Martínez-Herrera
  3. CIBER CB06/04/0071 Research Group. CIBER Hepatic and Digestive Diseases, University of Valencia, Av Blasco Ibáñez 13, 46010, Valencia, Spain

    • Víctor M. Víctor
    •  & Milagros Rocha
  4. Department of Physiology, University of Valencia, Av. Blasco Ibáñez 13, 46010, Valencia, Spain

    • Víctor M. Víctor

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Víctor M. Víctor or Milagros Rocha.

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DOI

https://doi.org/10.1038/s41366-018-0309-5