Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework

Samantha M Solon-Biet; Victoria C Cogger; Tamara Pulpitel; Marika Heblinski; Devin Wahl; Aisling C McMahon; Alessandra Warren; Jessica Durrant-Whyte; Kirsty A Walters; James R Krycer; Fleur Ponton; Rahul Gokarn; Jibran A Wali; Kari Ruohonen; Arthur D Conigrave; David E James; David Raubenheimer; Christopher D Morrison; David G Le Couteur; Stephen J Simpson

doi:10.1016/j.cmet.2016.09.001

Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework

Cell Metab. 2016 Oct 11;24(4):555-565. doi: 10.1016/j.cmet.2016.09.001. Epub 2016 Sep 29.

Authors

Samantha M Solon-Biet¹, Victoria C Cogger², Tamara Pulpitel³, Marika Heblinski⁴, Devin Wahl⁵, Aisling C McMahon⁵, Alessandra Warren⁶, Jessica Durrant-Whyte⁴, Kirsty A Walters⁷, James R Krycer³, Fleur Ponton⁸, Rahul Gokarn⁶, Jibran A Wali⁵, Kari Ruohonen⁹, Arthur D Conigrave¹⁰, David E James¹¹, David Raubenheimer¹², Christopher D Morrison¹³, David G Le Couteur², Stephen J Simpson¹⁴

Affiliations

¹ 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.
² 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.
³ Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; School of Life and Environmental Sciences, University of Sydney, Sydney 2006, Australia.
⁴ Charles Perkins Centre, University of Sydney, Sydney 2006, Australia.
⁵ 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.
⁶ Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney 2139, Australia.
⁷ 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.
⁸ Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Department of Biological Sciences, Macquarie University, Sydney NSW 2109, Australia.
⁹ Cargill Aqua Nutrition, 4327 Sandnes, Norway.
¹⁰ 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.
¹¹ 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.
¹² Charles Perkins Centre, University of Sydney, Sydney 2006, Australia; Faculty of Veterinary Science, University of Sydney, Sydney 2006, Australia.
¹³ Pennington Biomedical Research Center (PBRC), Baton Rouge, LA 70808, USA.
¹⁴ 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.

PMID: 27693377
DOI: 10.1016/j.cmet.2016.09.001

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factors / genetics
Activating Transcription Factors / metabolism
Animal Nutritional Physiological Phenomena*
Animals
Appetite
Dietary Proteins / metabolism
Energy Metabolism
Female
Fibroblast Growth Factors / blood
Fibroblast Growth Factors / metabolism*
Gene Expression Regulation
Glucose / metabolism
Insulin-Like Growth Factor I / metabolism
Male
Mice, Inbred C57BL
Models, Biological
Phenotype
Uncoupling Protein 1 / metabolism

Substances

Activating Transcription Factors
Atf5 protein, mouse
Dietary Proteins
Uncoupling Protein 1
fibroblast growth factor 21
Fibroblast Growth Factors
Insulin-Like Growth Factor I
Glucose