TY - JOUR
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, Enzo
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 - Muller, Oliver J.
AU - Rose, Adam J.
N1 - Funding Information:
The authors wish to thank former lab members Thomas Gantert and Adriano Maida (German Cancer Research Center, Heidelberg, Germany) who conducted the pilot experiments for this study series. The experimental and technical assistance of Robert Lee (Monash Metabolic Phenotyping Facility, Australia), Anja Pfenninger (Sanofi-Aventis, Germany), Annika Zota, Max Schuster, and Sarah Lerch (German Cancer Research Center, Germany) is gratefully acknowledged. These studies were supported by Monash Biomedicine Discovery Institute laboratory start-up funds to A.J.R. as well as a Monash Joint Science-Medicine Interdisciplinary Research Seed Funding to A.J.R. and M.D.W.P.
Publisher Copyright:
© 2020, The Author(s).
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.
KW - gastrointestinal hormones
KW - homeostasis
UR - http://www.scopus.com/inward/record.url?scp=85086105712&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16568-z
DO - 10.1038/s41467-020-16568-z
M3 - Article
C2 - 32518324
AN - SCOPUS:85086105712
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2894
ER -
