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


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.

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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.

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Correspondence to Daniel de Luis.

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15-Hydroxyicosatetraenoic acid




14-Hydroxy docosahexaenoic acid


14-Hydroxy docosahexaenoic acid


15-Hydroxyicosatetraenoic acid




17-Hydroxy docosahexaenoic acid


17-Hydroxy docosahexaenoic acid


4-Hydroxy docosahexaenoic acid


4-Hydroxy docosahexaenoic acid


5-Hydroxyicosatetraenoic acid




7-Hydroxy docosahexaenoic acid


7-Hydroxy docosahexaenoic acid


Nuclear matrix-associated protein RMAR1


Nuclear matrix-associated protein SMAR1


8-Hydroxyicosatetraenoic acid


Arachidonic acid


Available data only


Anti-inflammatory fatty acid index


Analysis of covariance




Body mass index






C-reactive protein


Docosahexaenoic acid


Docosapentaenoic acid


Eicosapentaenoic acid


Fatty acid methyl ester


Gas chromatograph/mass spectrometer


High-density lipoprotein


Homeostatic model assessment of insulin resistance


High-performance liquid chromatography


Interleukin 6


K2-Ethylenediaminetetraacetic acid


Liquid chromatography


Low-density lipoprotein


Lipid mediators




Leukotriene B4


Nuclear matrix-associated protein MAR1


Mass spectrometry


Monounsaturated fatty acid


Not significant


Programmed cell death protein 1


Prostaglandin E2




Polyunsaturated fatty acid


Red blood cell


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


Standard deviation


Saturated fatty acid


Proresolution lipid mediators


Tumor necrosis factor


T-box transcription factor


Very low-calorie ketogenic diet


Waist circumference

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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

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