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; Adam J. Rose

doi:10.1038/s41467-020-16568-z

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, Adam J. Rose^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

75 Citations (Scopus)

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.

Original language	English
Article number	2894
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16568-z
Publication status	Published - 1 Dec 2020

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Yap, Y. W., Rusu, P. M., Chan, A. Y., Fam, B. C., Jungmann, A., Solon-Biet, S. M., Barlow, C. K., Creek, D. J., Huang, C., Schittenhelm, R. B., Morgan, B., Schmoll, D., Kiens, B., Piper, M. D. W., Heikenwälder, M., Simpson, S. J., Bröer, S., Andrikopoulos, S., Müller, O. J., & Rose, A. J. (2020). Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. Nature Communications, 11(1), Article 2894. https://doi.org/10.1038/s41467-020-16568-z

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title = "Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution",

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.",

author = "Yap, {Yann W.} and Rusu, {Patricia M.} and Chan, {Andrea Y.} and Fam, {Barbara C.} and Andreas Jungmann and Solon-Biet, {Samantha M.} and Barlow, {Christopher K.} and Creek, {Darren J.} and Cheng Huang and Schittenhelm, {Ralf B.} and Bruce Morgan and Dieter Schmoll and Bente Kiens and Piper, {Matthew D.W.} and Mathias Heikenw{\"a}lder and Simpson, {Stephen J.} and Stefan Br{\"o}er and Sofianos Andrikopoulos and M{\"u}ller, {Oliver J.} and Rose, {Adam J.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16568-z",

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Yap, YW, Rusu, PM, Chan, AY, Fam, BC, Jungmann, A, Solon-Biet, SM, Barlow, CK, Creek, DJ, Huang, C, Schittenhelm, RB, Morgan, B, Schmoll, D, Kiens, B, Piper, MDW, Heikenwälder, M, Simpson, SJ, Bröer, S, Andrikopoulos, S, Müller, OJ & Rose, AJ 2020, 'Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution', Nature Communications, vol. 11, no. 1, 2894. https://doi.org/10.1038/s41467-020-16568-z

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T1 - Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution

AU - Yap, Yann W.

AU - Rusu, Patricia M.

AU - Chan, Andrea Y.

AU - Fam, Barbara C.

AU - Jungmann, Andreas

AU - Solon-Biet, Samantha M.

AU - Barlow, Christopher K.

AU - Creek, Darren J.

AU - Huang, Cheng

AU - Schittenhelm, Ralf B.

AU - Morgan, Bruce

AU - Schmoll, Dieter

AU - Kiens, Bente

AU - Piper, Matthew D.W.

AU - Heikenwälder, Mathias

AU - Simpson, Stephen J.

AU - Bröer, Stefan

AU - Andrikopoulos, Sofianos

AU - Müller, Oliver J.

AU - Rose, Adam J.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-020-16568-z

DO - 10.1038/s41467-020-16568-z

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2894

ER -

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

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