Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework.
Fibroblast growth factor 21 (FGF21) is the first known endocrine signal activated by protein restriction. Although FGF21 is robustly elevated in low-protein environments, increased FGF21 is also seen in various other contexts such as fasting, overfeeding, ketogenic diets, and high-carbohydrate diets, leaving its nutritional context and physiological role unresolved and controversial. Here, we use the Geometric Framework, a nutritional modeling platform, to help reconcile these apparently conflicting findings in mice confined to one of 25 diets that varied in protein, carbohydrate, and fat content. We show that FGF21 was elevated under low protein intakes and maximally when low protein was coupled with high carbohydrate intakes. Our results explain how elevation of FGF21 occurs both under starvation and hyperphagia, and show that the metabolic outcomes associated with elevated FGF21 depend on the nutritional context, differing according to whether the animal is in a state of under- or overfeeding.
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia.
Samantha M
SM
Solon-Biet
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia; Faculty of Medicine, University of Sydney, Sydney 2006, Australia.
Victoria C
VC
Cogger
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia.
Tamara
T
Pulpitel
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia.
Marika
M
Heblinski
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia.
Devin
D
Wahl
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia.
Aisling C
AC
McMahon
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia.
Alessandra
A
Warren
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia.
Jessica
J
Durrant-Whyte
ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia; School of Women's and Children's Health, Discipline of Obstetrics and Gynaecology, University of New South Wales, Sydney 2052, Australia.
Kirsty A
KA
Walters
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia.
James R
JR
Krycer
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Department of Biological Sciences, Macquarie University, Sydney NSW 2109, Australia.
Fleur
F
Ponton
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia.
Rahul
R
Gokarn
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia.
Jibran A
JA
Wali
Cargill Aqua Nutrition, 4327 Sandnes, Norway.
Kari
K
Ruohonen
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Faculty of Medicine, University of Sydney, Sydney 2006, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia.
Arthur D
AD
Conigrave
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia; Sydney Medical School, University of Sydney, Sydney 2006, Australia.
David E
DE
James
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Faculty of Veterinary Science, University of Sydney, Sydney 2006, Australia.
David
D
Raubenheimer
Pennington Biomedical Research Center (PBRC), Baton Rouge, LA 70808, USA.
Christopher D
CD
Morrison
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia; Faculty of Medicine, University of Sydney, Sydney 2006, Australia.
David G
DG
Le Couteur
Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia. Electronic address: stephen.simpson@sydney.edu.au.
Stephen J
SJ
Simpson
D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001066:Appetite; D004044:Dietary Proteins / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010641:Phenotype; D000071256:Uncoupling Protein 1 / Q000378:metabolism
D051696:Activating Transcription Factors; C471855:Atf5 protein, mouse; D004044:Dietary Proteins; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D005947:Glucose