Effect of DHA supplementation in a very low-calorie ketogenic diet in the treatment of obesity: a randomized clinical trial

Abstract

A VLCK diet supplemented with DHA, commercially available, was tested against an isocaloric VLCK diet without DHA. The main purpose of this study was to compare the effect of DHA supplementation in classic cardiovascular risk factors, adipokine levels, and inflammation-resolving eicosanoids. A total of obese patients were randomized into two groups: a group supplemented with DHA (n = 14) (PnK-DHA group) versus a group with an isocaloric diet free of supplementation (n = 15) (control group). The follow-up period was 6 months. The average weight loss after 6 months of treatment was 20.36 ± 5.02 kg in control group and 19.74 ± 5.10 kg in PnK-DHA group, without statistical differences between both groups. The VLCK diets induced a significant change in some of the biological parameters, such as insulin, HOMA-IR, triglycerides, LDL cholesterol, C-reactive protein, resistin, TNF alpha, and leptin. Following DHA supplementation, the DHA-derived oxylipins were significantly increased in the intervention group. The ratio of proresolution/proinflammatory lipid markers was increased in plasma of the intervention group over the entire study. Similarly, the mean ratios of AA/EPA and AA/DHA in erythrocyte membranes were dramatically reduced in the PnK-DHA group and the anti-inflammatory fatty acid index (AIFAI) was consistently increased after the DHA treatment (p < 0.05). The present study demonstrated that a very low-calorie ketogenic diet supplemented with DHA was significantly superior in the anti-inflammatory effect, without statistical differences in weight loss and metabolic improvement.

This is a preview of subscription content, log in to check access.

Fig. 1

References

  1. 1.

    K.M. Flegal, M.D. Carroll, B.K. Kit, C.L. Ogden, Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA 307, 491–497 (2012)

    Article  PubMed  Google Scholar 

  2. 2.

    L. Fontana, S. Klein, Aging, adiposity, and calorie restriction. JAMA 297, 986–994 (2007)

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    F.B. Hu, J.B. Meigs, T.Y. Li, Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 53, 693–700 (2004)

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    E.W. Gregg, H. Chen, L.E. Wagenknecht, J.M. Clark, L.M. Delahanty, Bantle et al., JLook AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA 308, 2489–2496 (2012)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    L. Sjöström, M. Peltonen, P. Jacobson, C.D. Sjöström, K. Karason, H. Wedel et al., Bariatric surgery and long-term cardiovascular events. JAMA 307, 56–65 (2012)

    Article  PubMed  Google Scholar 

  6. 6.

    G.B. Dodell, J.B. Albu, L. Attia, J. McGinty, F.X. Pi-Sunyer, B. Laferrère, The bariatric surgery patient: lost to follow-up; from morbid obesity to severe malnutrition. Endocr. Pract. 18, 21–25 (2012)

    Article  Google Scholar 

  7. 7.

    W.P. James, I.D. Caterson, W. Coutinho, N. Finer, Gaal L.F. Van, SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N. Engl. J. Med. 363, 905–917 (2010)

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    J.C. Halford, E.J. Boyland, J.E. Blundell, T.C. Kirkham, J.A. Harrold, Pharmacological management of appetite expression in obesity. Nat. Rev. Endocrinol. 6, 255–269 (2010)

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    J.A. Harrold, T.M. Dovey, J.E. Blundell, J.C. Halford, CNS regulation of appetite. Neuropharmacology 63, 3–17 (2012)

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    T.P. Wycherley, L.J. Moran, P.M. Clifton, M. Noakes, G.D. Brinkworthand, 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. 96, 1281–1298 (2012)

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    T.A. Hussain, T.C. Mathew, A.A. Dashti, S. Asfar, N. Al-Zaid, H.M. Dashti, Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition 28, 1016–1021 (2012)

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    B. Moreno, D. Bellido, I. Sajoux, A. Goday, D. Saavedra, A. Crujeiras, F. Casanueva, Comparison of a very low-calorie-ketogenic diet with a standard low-calorie diet in the treatment of obesity. Endocrine 47(3), 793–805 (2014)

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Bakker GC, van Erk MJ, pellins L, Wopereis S, Rubing CM. AN anti-inflammatory dietary mix modulates inflammation and oxidative and metabolic stress In overweight men: a nutrigenomic approach. Am J CLin Nutr 2010:91:1044-1059

  14. 14.

    R.F. Grimble, Dietary lipids and the inflammatory response. Proc. Nutr. Soc. 57, 535–537 (1998)

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    C.N. Serhan, N. Chiang, endogenous pro-resolving and anti-inflammatory lipid mediators; a new pharmacological genus. Br. J. Pharmacol. 153(suppl 1), S200–S215 (2008)

    CAS  PubMed  Google Scholar 

  16. 16.

    http://pronokalgroup.com/

  17. 17.

    SCOOP-VLCD task 7.3. Reports on tasks for scientific cooperation. Collection of data on products intended for use in very-low-calorie-diets. Report. Brussels. European Commission, September 2002

  18. 18.

    P. Le Faouder, V. Baillif, I. Spreadbury, J.P. Motta, P. Rousset, G. Chêne et al., LC-MS/MS method for rapid and concomitant quantification of pro-inflammatory and pro-resolving polyunsaturated fatty acid metabolites. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 932, 123–133 (2013)

    Article  PubMed  Google Scholar 

  19. 19.

    M.J. Duart, C.O. Arroyo, J.L. Moreno, Validation of a insulin model for the reactions in RIA. Clin. Chem. Lab. Med. 40, 1161–1167 (2002)

    Article  Google Scholar 

  20. 20.

    D.R. Mathews, J.P. Hosker, A.S. Rudenski et al., Homeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–414 (1985)

    Article  Google Scholar 

  21. 21.

    A. Pfutzner, M. Langefeld, T. Kunt et al., Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Clin. Lab. 49, 571–576 (2003)

    PubMed  Google Scholar 

  22. 22.

    U. Meier, M. Gressner, Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, Ghrelin, adiponectin, and resistin. Clin. Chem. 50, 1511–1525 (2004)

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    P. Suominen, Evaluation of an enzyme immunometric assay to measure serum adiponectin concentrations. Clin. Chem. 50, 219–221 (2004)

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    G. Lepage, C.C. Roy, Direct transesterification of all classes of lipids in a one-step reaction. J. Lipid Res. 27, 114–120 (1986)

    CAS  PubMed  Google Scholar 

  25. 25.

    W.S. Harris, The omega-3 index as a risk factor for coronary heart disease. Am. J. Clin. Nutr. 87(6), 1997S–2002S (2008)

    CAS  PubMed  Google Scholar 

  26. 26.

    T. Grimstad, R.K. Berge, P. Bohov, J. Skorve, L. Goransson, R. Omdal et al., Salmon diet in patients with active ulcerative colitis reduced the simple clinical colitis activity index and increased the anti-inflammatory fatty acid index—a pilot study. Scand. J. Clin. Lab. Investig. 71(68–73), 32 (2011)

    Google Scholar 

  27. 27.

    B.T. Kalish, H.D. Le, J.M. Fitzgerald, S. Wang, K. Seamon, K.M. Gura et al., Intravenous fish oil lipid emulsion promotes a shift toward anti-inflammatory proresolving lipid mediators. Am. J. Physiol. Gastrointest. Liver Physiol. 305(11), G818–G828 (2013)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    T.A. Wadden, R.H. Neiberg, R.R. Wing, J.M. Clark, L.M. Delahanty, J.O. Hill et al., Four-year weight losses in the look AHEAD study: factors associated with long-term success. Obesity (Silver Spring) 19, 1987–1998 (2011)

    Article  PubMed Central  Google Scholar 

  29. 29.

    L. Sjöström, A. Rissanen, T. Andersen, M. Boldrin, A. Golay, H.P. Koppeschaar, M. Krempf, Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Eur. Multicen. Orlistat Study Group Lancet 352, 167–172 (1998)

    Google Scholar 

  30. 30.

    J.P. Despres, A. Golay, L. Sjostrom, Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 353, 2121–2134 (2005)

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    L.F. Van Gaal, A.M. Rissanen, A.J. Scheen, O. Ziegler, S. Rossner, For the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1 year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005)

    Article  PubMed  Google Scholar 

  32. 32.

    S. Smith, N.J. Weissman, C.M. Anderson, M. Sanchez, E. Chuang, S. Subbe et al., Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med. 363, 245–256 (2010)

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    M. Glandt, I. Raz, Present and future: pharmacologic treatment of Obesity. J. Obes. (2011). doi:10.1155/2011/636181

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    G.A. Bray, D.H. Ryan, D. Gordon, S. Heidingsfelder, F. Cerise, K. Wilson, A double-blind randomized placebo-controlled trial of sibutramine. Obes. Res. 4, 263–270 (1996)

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    T. Okasaki, E. Himeno, H. Nanri, H. Ogata, M. Ikeda, Efects of mild aerobic exercise and a mild hypocaloric diet on plasma leptin in sedentary women. Clin. exp. Pharmacol. 26, 415–420 (1999)

    Article  Google Scholar 

  36. 36.

    J.P. Bastard, C. Jardel, E. Bruckert, Elevated levels of interleukin-6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J. Clin. Endocrinol. Metab. 85, 3338–3342 (2000)

    CAS  PubMed  Google Scholar 

  37. 37.

    K. Hotta, T. Funahashi, Y. Arita, Plasma concentrations of a novel, adipose specific protein, adiponectin in tyoe 2 patients. Arterioscler. Thromb. Vasc. 20, 1595 (2000)

    CAS  Article  Google Scholar 

  38. 38.

    C. Xenachis, E. Samojlik, M.P. Raghuwanshi, M.A. Kirschner, Leptin, insulin and TNF-alpha in weight loss. J. Endocrinol. Investig. 24, 865–870 (2001)

    CAS  Article  Google Scholar 

  39. 39.

    L.U. Monzillo, O. Hamdy, E.S. Horton, S. Ledbury, C. Mulloly, C. Jarema, S. Porter, K. Ovalle, Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Obes. Res. 11, 1048–1052 (2003)

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    G. Schmitz, J. Ecker, The opposing effects of n − 3 and n − 6 fatty acids. Prog. Lipid Res. 47(2), 147–155 (2008)

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    J. Faber, M. Berkhout, A.P. Vos, J.W. Sijben, P.C. Calder, J. Garssen et al., Supplementation with a fish oil-enriched, high-protein medical food leads to rapid incorporation of EPA into white blood cells and modulates immune responses within one week in healthy men and women. J. Nutr. 141(5), 964–970 (2011)

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    M.J. James, R.A. Gibson, L.G. Cleland, Dietary polyunsaturated fatty acids and inflammatory mediator production. Am. J. Clin. Nutr. 71(1 Suppl), 343S–348S (2000)

    CAS  PubMed  Google Scholar 

  43. 43.

    M. Spite, J. Clària, C.N. Serhan, Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab. 19(1), 21–36 (2014)

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    C.N. Serhan, Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu. Rev. Immunol. 25, 101–137 (2007)

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    M.J. Zhang, M. Spite, Resolvins: anti-inflammatory and proresolving mediators derived from omega-3 polyunsaturated fatty acids. Annu. Rev. Nutr. 32, 203–227 (2012)

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    P. Flachs, R. Rühl, M. Hensler, P. Janovska, P. Zouhar, V. Kus et al., Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids. Diabetologia 54(10), 2626–2638 (2011)

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge PNKDIET, SLU, Spain, for providing free of charge the diet of the ketogenic phases in both groups and oral supplementation of DHA or placebo.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Daniel de Luis.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Glossary

12-HETE

15-Hydroxyicosatetraenoic acid

12-LOX

12-Lipoxygenase

14-HDOHE

14-Hydroxy docosahexaenoic acid

14-HDHA

14-Hydroxy docosahexaenoic acid

15-HETE

15-Hydroxyicosatetraenoic acid

15-LOX

12-Lipoxygenase

17-HDOHE

17-Hydroxy docosahexaenoic acid

17-HDHA

17-Hydroxy docosahexaenoic acid

4-HDOHE

4-Hydroxy docosahexaenoic acid

4-HDHA

4-Hydroxy docosahexaenoic acid

5-HETE

5-Hydroxyicosatetraenoic acid

5-LOX

5-Lipoxygenase

7-HDOHE

7-Hydroxy docosahexaenoic acid

7-HDHA

7-Hydroxy docosahexaenoic acid

7RMAR1

Nuclear matrix-associated protein RMAR1

7SMAR1

Nuclear matrix-associated protein SMAR1

8-HETE

8-Hydroxyicosatetraenoic acid

AA

Arachidonic acid

ADO

Available data only

AIFAI

Anti-inflammatory fatty acid index

ANCOVA

Analysis of covariance

BHT

Butylhydroxytoluene

BMI

Body mass index

CHOL

Cholesterol

COX

Cyclooxygenase

CRP

C-reactive protein

DHA

Docosahexaenoic acid

DPA

Docosapentaenoic acid

EPA

Eicosapentaenoic acid

FAME

Fatty acid methyl ester

GCMS

Gas chromatograph/mass spectrometer

HDL

High-density lipoprotein

HOMA-IR

Homeostatic model assessment of insulin resistance

HPLC

High-performance liquid chromatography

IL6

Interleukin 6

K2-EDTA

K2-Ethylenediaminetetraacetic acid

LC

Liquid chromatography

LDL

Low-density lipoprotein

LM

Lipid mediators

LOX

Lipoxygenase

LTB4

Leukotriene B4

MAR1

Nuclear matrix-associated protein MAR1

MS

Mass spectrometry

MUFA

Monounsaturated fatty acid

NS

Not significant

PD1

Programmed cell death protein 1

PGE2

Prostaglandin E2

PnK

Pronokal

PUFA

Polyunsaturated fatty acid

RBC

Red blood cell

RVD2

7(S), 16(R), 17(S)-resolvin D2

SD

Standard deviation

SFA

Saturated fatty acid

SPM

Proresolution lipid mediators

TNF

Tumor necrosis factor

TXB2

T-box transcription factor

VLKD

Very low-calorie ketogenic diet

WC

Waist circumference

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Luis, D., Domingo, J.C., Izaola, O. et al. Effect of DHA supplementation in a very low-calorie ketogenic diet in the treatment of obesity: a randomized clinical trial. Endocrine 54, 111–122 (2016). https://doi.org/10.1007/s12020-016-0964-z

Download citation

Keywords

  • DHA
  • Ketosis
  • Protein diet
  • Weight loss
  • Pronokal method
  • PnK method