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Endocrine

, Volume 54, Issue 1, pp 111–122 | Cite as

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

  • Daniel de LuisEmail author
  • Joan Carles Domingo
  • Olatz Izaola
  • Felipe F. Casanueva
  • Diego Bellido
  • Ignacio Sajoux
Original Article

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.

Keywords

DHA Ketosis Protein diet Weight loss Pronokal method PnK method 

Notes

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.

Compliance with ethical standards

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

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)CrossRefPubMedGoogle Scholar
  2. 2.
    L. Fontana, S. Klein, Aging, adiposity, and calorie restriction. JAMA 297, 986–994 (2007)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedPubMedCentralGoogle 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)CrossRefPubMedGoogle 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)CrossRefGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle Scholar
  9. 9.
    J.A. Harrold, T.M. Dovey, J.E. Blundell, J.C. Halford, CNS regulation of appetite. Neuropharmacology 63, 3–17 (2012)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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 2010:91:1044-1059Google Scholar
  14. 14.
    R.F. Grimble, Dietary lipids and the inflammatory response. Proc. Nutr. Soc. 57, 535–537 (1998)CrossRefPubMedGoogle 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)PubMedGoogle Scholar
  16. 16.
  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 2002Google Scholar
  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)CrossRefPubMedGoogle 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)CrossRefGoogle 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)CrossRefGoogle 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)PubMedGoogle 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)CrossRefPubMedGoogle Scholar
  23. 23.
    P. Suominen, Evaluation of an enzyme immunometric assay to measure serum adiponectin concentrations. Clin. Chem. 50, 219–221 (2004)CrossRefPubMedGoogle 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)PubMedGoogle 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)PubMedGoogle 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)CrossRefPubMedPubMedCentralGoogle 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)CrossRefPubMedCentralGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle Scholar
  33. 33.
    M. Glandt, I. Raz, Present and future: pharmacologic treatment of Obesity. J. Obes. (2011). doi: 10.1155/2011/636181 PubMedPubMedCentralGoogle 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)CrossRefPubMedGoogle 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)CrossRefGoogle 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)PubMedGoogle 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)CrossRefGoogle 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)CrossRefGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)PubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle 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)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Daniel de Luis
    • 1
    Email author
  • Joan Carles Domingo
    • 2
  • Olatz Izaola
    • 1
  • Felipe F. Casanueva
    • 3
  • Diego Bellido
    • 4
  • Ignacio Sajoux
    • 5
  1. 1.Department of Endocrinology and Nutrition, School of Medicine, Center of Investigation of Endocrinology and Nutrition, Hospital Clinico Universitario ValladolidUniversity of ValladolidSimancasSpain
  2. 2.Department of Biochemistry and Molecular Biology, School of BiologyUniversity of BarcelonaBarcelonaSpain
  3. 3.Division of Endocrinology, Department of Medicine, Complejo Hospitalario Universitario de SantiagoSantiago de Compostela University and CIBER Fisiopatología Nutrición y ObesidadSantiago De CompostelaSpain
  4. 4.Division of EndocrinologyComplejo Hospitalario Universitario de Ferrol and Coruña UniversityFerrolSpain
  5. 5.Medical Department Pronokal GroupPronokalGroupBarcelonaSpain

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