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Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial

Abstract

Purpose

Calorie restriction (CR) is an effective treatment for obesity-related liver and metabolic disease. However, CR studies in individuals without obesity are needed to see if CR could delay disease onset. Liver biomarkers indicate hepatic health and are linked to cardiometabolic disease. Our aim was to examine the effects of a 2-year CR intervention on liver biomarkers in healthy individuals without obesity.

Methods

The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was a 2-year randomized controlled trial. Overall, 218 participants (body mass index: 25.1 ± 1.7 kg/m2) were enrolled into a control group (n = 75) that ate ad libitum (AL), or a CR group (n = 143) that aimed to decrease energy intake by 25%. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and bilirubin were measured during the trial.

Results

At month 24, relative to the AL group, ALP (− 7 ± 1 IU/L; P < 0.01) and GGT (− 0.11 ± 0.04 log IU/L; P = 0.02) decreased and bilirubin increased (0.21 ± 0.06 log mg/dL; P < 0.01) in the CR group; no between-group differences in ALT (− 1 ± 1 IU/L; P > 0.99) or AST (2 ± 2 IU/L; P = 0.68) were revealed. However, sex-by-treatment-by-time interactions (P < 0.01) were observed, with CR (vs. control) inducing reduced ALT and GGT and increased AST in men only (P ≤ 0.02).

Conclusions

In metabolically healthy individuals without obesity, 2 years of CR improves several liver biomarkers, with potentially greater improvements in men. These data suggest that sustained CR may improve long-term liver and metabolic disease risk in healthy adults.

Trial registration

Clinicaltrials.gov (NCT00427193). Registered January 2007.

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Availability of data and material

Individual de-identified participant data will not be shared, but data can be freely downloaded via the CALERIE website (http://calerie.duke.edu).

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Acknowledgements

We are indebted to the study participants who invested over 2 years to participate in this trial.

Funding

The research was supported by the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Grants U01AG022132, U01AG020478, U01AG020487, and U01AG020480); National Obesity Research Center (Grant P30 DK072476), sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center (Grant 1 U54 GM104940). The work was also supported by the American Heart Association (Grant #20POST35210907) (J.L.D). C. H is supported by a National Institutes of Health National Research Service Award (T32 DK064584). The funder for this exploratory analysis had a role in study design and data collection, but no role in data analysis, data interpretation, or writing of the manuscript. The corresponding author had access to all the data and had final responsibility for the decision to submit for publication.

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Contributions

ER, LMR, KMH, SBR, SKD, WEK, and CKM were responsible for study design and collection of study data. JLD conceived analysis, originally drafted the manuscript, and revised the manuscript. JWA, CH, and CKM contributed to drafting of the manuscript. MB curated data and conducted statistical analyses. All authors reviewed the final manuscript and approved the contents.

Corresponding author

Correspondence to James L. Dorling.

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Conflict of interest

All authors declare no conflicts of interest relevant to the study.

Ethical approval

All CALERIE institutions received institutional review board approval. CALERIE was performed in line with the ethical standards cited in the 1964 Declaration of Helsinki and its later amendments.

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All participants provided written informed consent before their inclusion in the study.

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All authors agreed with the content of the manuscript and gave consent to submit.

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Dorling, J.L., Ravussin, E., Redman, L.M. et al. Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial. Eur J Nutr 60, 1633–1643 (2021). https://doi.org/10.1007/s00394-020-02361-7

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  • DOI: https://doi.org/10.1007/s00394-020-02361-7

Keywords

  • Energy restriction
  • Liver enzymes
  • Bilirubin
  • Cardiometabolic health
  • Aging