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

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 Morgan, Dieter Schmoll, Bente Kiens, Matthew D. W. Piper, Mathias Heikenwälder, Stephen J. Simpson, Stefan Bröer, Sofianos Andrikopoulos, Oliver J. Müller and Adam J. Rose ()
Additional contact information
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
Samantha M. Solon-Biet: University of Sydney
Christopher K. Barlow: Monash University
Darren J. Creek: 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)
Adam J. Rose: Monash University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16568-z

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