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Effect of a plant-based, low-fat diet versus an animal-based, ketogenic diet on ad libitum energy intake

Nature Medicine volume 27, pages 344–353 (2021)Cite this article

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Abstract

The carbohydrate–insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m−2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal−1) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal−1) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d−1 less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d−1 less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate–insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108.

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Fig. 1: Overview of the study design, participant flow and baseline information.
Fig. 2: Ad libitum food intake and body composition change.
Fig. 3: Continuous glucose monitoring and daily capillary β-hydroxybutyrate.
Fig. 4: LC and LF meal tests.

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Data availability

The study protocol, de-identified individual data, and statistical analysis code for the results reported in this manuscript will be posted on the Open Science Framework website (https://osf.io/fjykq/) and is freely available without restrictions.

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Acknowledgements

This work was supported by the Intramural Research Program of the NIH, National Institute of Diabetes & Digestive & Kidney Diseases under award number 1ZIADK013037. P.V.J. is supported by the National Institute of Nursing Research under award number 1ZIANR000035-01, The Office of Workforce Diversity and the Rockefeller University Heilbrunn Nurse Scholar Award. We thank the nursing and nutrition staff at the NIH Metabolic Clinical Research Unit for their invaluable assistance with this study. We thank K. Klatt, J. Speakman and E. Weiss for helpful comments. We thank the study participants who volunteered to participate in this demanding protocol.

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Authors and Affiliations

  1. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA

    Kevin D. Hall, Juen Guo, Amber B. Courville, Robert Brychta, Kong Y. Chen, Valerie Darcey, Ahmed M. Gharib, Isabelle Gallagher, Rebecca Howard, Lauren Milley, Ronald Ouwerkerk, Irene Rozga, Alex Schick, Michael Stagliano, Mary Walter, Peter Walter & Stephanie T. Chung

  2. National Institutes of Health Clinical Center, Bethesda, MD, USA

    James Boring, Klaudia Raisinger, Stephan Torres & Shanna Yang

  3. Singapore Institute for Food and Biotechnology Innovation, Singapore, Singapore

    Ciaran G. Forde

  4. National Institute of Nursing Research, Bethesda, MD, USA

    Paule V. Joseph

  5. National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

    Paule V. Joseph

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  1. Kevin D. Hall
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Contributions

K.D.H. designed the study. K.D.H. and J.G. analyzed the data. A.C. and S.Y. designed the diets and measured food and beverage intake with the assistance of J.B. and S.T. R.B. and K.Y.C. performed the indirect calorimetry measurements. C.G.F. assisted with the appetitive and eating rate measurements and their interpretation. A.M.G. and R.O. performed the liver fat measurements. M.W. and P.W. analyzed the blood and urine samples. S.T.C., I.R. and M.S. were responsible for the clinical care of the research participants and supervised the day-to-day operation and coordination of the study by V.D., I.G., R.H., L.M., P.V.J., K.R. and A.S. K.D.H. wrote the manuscript and is the guarantor of this work and has full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors critically revised the draft and approved the final manuscript.

Corresponding author

Correspondence to Kevin D. Hall.

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Competing interests

C.G. Forde has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, serves on the scientific advisory council for Kerry Taste and Nutrition and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. The other authors declare no competing interests.

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Peer review information Jennifer Sargent was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Oral glucose tolerance.

Mean blood concentrations in response to 75g oral glucose tolerance tests conducted at the end of the LC and LF diet periods (n=20) with respect to a) glucose, b) insulin, c) lactate, and d) free fatty acids. Data are presented as mean ± SEM.

Supplementary information

Supplementary Information

Descriptions and photographs of seven daily menus for LC and LF diets plus snacks.

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Hall, K.D., Guo, J., Courville, A.B. et al. Effect of a plant-based, low-fat diet versus an animal-based, ketogenic diet on ad libitum energy intake. Nat Med 27, 344–353 (2021). https://doi.org/10.1038/s41591-020-01209-1

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