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Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution

Author

Listed:
  • Yann W. Yap

    (Monash University)

  • Patricia M. Rusu

    (Monash University)

  • Andrea Y. Chan

    (Monash University)

  • Barbara C. Fam

    (University of Melbourne)

  • Andreas Jungmann

    (University Hospital Heidelberg
    German Center for Cardiovascular Research (DZHK))

  • Samantha M. Solon-Biet

    (University of Sydney)

  • Christopher K. Barlow

    (Monash University)

  • Darren J. Creek

    (Monash University
    Monash University)

  • Cheng Huang

    (Monash University)

  • Ralf B. Schittenhelm

    (Monash University)

  • Bruce Morgan

    (Saarland University)

  • Dieter Schmoll

    (Industriepark Hoechst)

  • Bente Kiens

    (University of Copenhagen)

  • Matthew D. W. Piper

    (Monash University)

  • Mathias Heikenwälder

    (German Cancer Research Center)

  • Stephen J. Simpson

    (University of Sydney)

  • Stefan Bröer

    (Australian National University)

  • Sofianos Andrikopoulos

    (University of Melbourne)

  • Oliver J. Müller

    (German Center for Cardiovascular Research (DZHK)
    University of Kiel)

  • Adam J. Rose

    (Monash University)

Abstract

Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

Suggested Citation

  • Yann W. Yap & Patricia M. Rusu & Andrea Y. Chan & Barbara C. Fam & Andreas Jungmann & Samantha M. Solon-Biet & Christopher K. Barlow & Darren J. Creek & Cheng Huang & Ralf B. Schittenhelm & Bruce Morg, 2020. "Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16568-z
    DOI: 10.1038/s41467-020-16568-z
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    Cited by:

    1. Tyler A. U. Hilsabeck & Vikram P. Narayan & Kenneth A. Wilson & Enrique M. Carrera & Daniel Raftery & Daniel Promislow & Rachel B. Brem & Judith Campisi & Pankaj Kapahi, 2024. "Systems biology approaches identify metabolic signatures of dietary lifespan and healthspan across species," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Cristal M. Hill & Diana C. Albarado & Lucia G. Coco & Redin A. Spann & Md Shahjalal Khan & Emily Qualls-Creekmore & David H. Burk & Susan J. Burke & J. Jason Collier & Sangho Yu & David H. McDougal & , 2022. "FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Yuqin Wu & Ashish Foollee & Andrea Y. Chan & Susanne Hille & Jana Hauke & Matthew P. Challis & Jared L. Johnson & Tomer M. Yaron & Victoria Mynard & Okka H. Aung & Maria Almira S. Cleofe & Cheng Huang, 2024. "Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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