ArticleCell metabolism2021
The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
Registry-linked trialOpen access · bronzeAbstract read
In one paragraph
Article in Cell metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07329088 (ISOLeucine Addition Treatment Effects), which is not on this map. Cited by 226 papers, 3 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
226citing papers in PubMed, 3 pooled it
21.5field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
ISOLeucine Addition Treatment Effects (ISOLATE) in a Controlled Diet Study
Who cites it
226 citing papers in PubMed, 3 syntheses or guidelines pooled it, 366 citations in OpenAlex.
- Efficacy of a High-Protein Diet to Lower Glycemic Levels in Type 2 Diabetes Mellitus: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Causal Relationship Between Branched-Chain Amino Acids and Hypertension: A Mendelian Randomization Study.Journal of the American Heart Association · 2024Pooled it
- Meta-analysis links dietary branched-chain amino acids to metabolic health in rodents.BMC biology · 2022Pooled it
- Exercise intensity determines circulating levels of Lac-Phe and other exerkines: a randomized crossover trial.Metabolomics : Official journal of the Metabolomic Society · 2025Trial
- A legume-enriched diet improves metabolic health in prediabetes mediated through gut microbiome: a randomized controlled trial.Nature communications · 2025Trial
- Association of Modifiable Lifestyle Factors with Plasma Branched-Chain Amino Acid Metabolites in Women.The Journal of nutrition · 2022Trial
- Article
- Macronutrient mixtures and interactions in health and disease.Nature reviews. Endocrinology · 2026Review
- High-protein diet promotes aging by activating the CG6415/AMT gene and disrupting mitochondrial homeostasis.Journal of advanced research · 2026Article
- Review
- Optimal standardized ileal digestible lysine levels in low-protein diets: Effects on performance of lactating sows and their offspring.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2026Article
- The emerging role of branched-chain amino acid metabolism in obesity.International journal of obesity (2005) · 2026Review
- Amino Acid Metabolism in Health and Disease.MedComm · 2026Review
- Oral‑gut axis in systemic disease: A barrier‑metabolism‑immunity three‑dimensional regulatory model (Review).International journal of molecular medicine · 2026Review
- The hallmarks of protein and amino acid restriction in aging and longevity.Cell press blue · 2026Article
- Using MetaboAnalyst 6.0 for exposomics data analysis-from LC-MS2 spectra processing to dose-response modeling and causal inference.Nature protocols · 2026Review
- Association of BCAAs/BCKAs with pancreatic steatosis in patients with type 2 diabetes mellitus: A cross-sectional study.Journal of diabetes investigation · 2026Article
- Plasma Metabolomic and Proteomic Profiling of the Mechanisms Underlying the Cumulative Impact of Co-occurring Psychiatric Disorders on Atopic Dermatitis.Acta dermato-venereologica · 2026Article
- Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.Nature aging · 2026Article
- Association Between Exposure to Multiple Metal Elements and Cognitive Function in Older Adults: The Mediating Role of Branched-Chain Amino Acids.Biological trace element research · 2026Article
166 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
27 authors at 4 institutions in 1 country.
Deyang YuWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
Nicole E RichardsonWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cara L GreenWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Alexandra B SpicerDepartment of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
Michaela E MurphyWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Victoria FloresWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cholsoon JangDepartment of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
Ildiko KaszaMcArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA.
Maria NikodemovaDepartment of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
Matthew H WakaiWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Jay L TomasiewiczWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Shany E YangWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Blake R MillerWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Heidi H PakWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Jacqueline A BrinkmanWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Jennifer M RojasDepartment of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
William J QuinnDepartment of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Eunhae P ChengWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Elizabeth N KononWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Lexington R HaiderWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Megan FinkeWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Michelle SonsallaWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Caroline M AlexanderMcArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53705, USA.
Joshua D RabinowitzDepartment of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Joseph A BaurDepartment of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
Kristen C MaleckiDepartment of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
Dudley W LammingWilliam S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular and Environmental Toxicology Program, University of Wisconsin-Madison, Madison, WI 53706, USA; Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI 53706, USA; Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA. Electronic address: dlamming@medicine.wisc.edu.
University of Wisconsin–Madison · USWilliam S. Middleton Memorial Veterans Hospital · USUniversity of Pennsylvania · USPrinceton University · US
Funding
UW COMPREHENSIVE CANCER CENTER SUPPORTP30CA014520 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI AMY TRENTHAM-DIETZ · 1985 to 2026
$142.6MVIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI MITCHELL A. LAZAR · 1986 to 2026
$48.3MBiology of Aging and Age-Related Diseases Training GrantT32AG000213 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI Rozalyn M. Anderson, Sanjay Asthana · 1991 to 2026
$9.9MMetabolism in Action: Quantitative Fluxes in MammalsDP1DK113643 · NIDDK · PRINCETON UNIVERSITY · PI RABINOWITZ, JOSHUA D · 2016 to 2020
$5.7MThe regulation of health and longevity by branched-chain amino acidsR01AG056771 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI Dudley William Lamming · 2018 to 2026
$3.1MSkin Diseases Research Center at the University of WisconsinP30AR066524 · NIAMS · UNIVERSITY OF WISCONSIN-MADISON · PI LONGLEY, B JACK · 2014 to 2018
$2.6MThe regulation of health and longevity by branched-chain amino acidsRF1AG056771 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI LAMMING, DUDLEY WILLIAM · 2023 to 2023
$2.1MComparative analysis of geroprotective interventions in established and novel mouse models of Alzheimer's diseaseR01AG062328 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI LAMMING, DUDLEY WILLIAM, MERRINS, MATTHEW J. · 2018 to 2022
$2.0MFunctional Dissection of Essential Wnt Signaling Receptors in Breast Stem CellsR01GM113142 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI ALEXANDER, CAROLINE M · 2016 to 2019
$1.3MThe regulation of health and longevity by branched-chain amino acidsR56AG056771 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI LAMMING, DUDLEY WILLIAM · 2017 to 2017
$573kTranslation analysis of a novel intervention for diet-induced obesityR21AG061635 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI COLMAN, RICKI J, LAMMING, DUDLEY WILLIAM · 2019 to 2020
$426kDistinct roles for calories, fasting, and mTOR in a calorie restricted dietF31AG066311 · NIA · UNIVERSITY OF WISCONSIN-MADISON · PI PAK, HEIDI HAYANG · 2019 to 2021
$92kBLRD VA I01 BX004031NCI NIH HHS P30 CA014520NIAMS NIH HHS P30 AR066524NIA NIH HHS F31 AG066311NIA NIH HHS R01 AG056771NIA NIH HHS R01 AG062328NIA NIH HHS R21 AG061635NIA NIH HHS R56 AG056771NIA NIH HHS RF1 AG056771NIA NIH HHS T32 AG000213NIDDK NIH HHS DP1 DK113643NIDDK NIH HHS P30 DK019525NIGMS NIH HHS R01 GM113142
Abstract
Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
Indexed as
DietAdipose Tissue, WhiteAmino Acids, Branched-ChainAnimalsBody Mass IndexEnergy MetabolismFibroblast Growth FactorsHumansIsoleucineLiverMaleMechanistic Target of Rapamycin Complex 1MiceMice, Inbred C57BLMice, KnockoutObesityAmino Acids, Branched-ChainEif2ak4 protein, mousefibroblast growth factor 21Fibroblast Growth FactorsIsoleucineMechanistic Target of Rapamycin Complex 1Protein Serine-Threonine KinasesUncoupling Protein 1Valinebody mass indexbranched-chain amino acidsdiabetesFGF21GCN2insulin resistanceisoleucinemTORC1obesityvaline
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Registered trials
NCT07329088ClinicalTrials.gov
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.