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Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
Open accessAbstract
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.
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In the citing paper
“a thorough analysis of macronutrient intake has revealed that fat intake does not significantly alter FGF21 expression in rodents28.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [28]
In the citing paper
“FGF21 is maximally induced under a nutritional state of a combined high-sugar/low-protein condition28.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [28]
In the citing paper
“maximal levels of circulating FGF21 increase in response to a combination of low-protein and high-carbohydrate conditions [152,158,165].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [152]
In the citing paper
“several recent studies confirmed that hepatic FGF21 increases in response to other nutritional stimuli, including conditions of macronutrient imbalance [152], and in response to alcohol intake [138,140,153].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [152]
In the citing paper
“Low-protein diets (73, 85), amino acid starvation (25, 121), and the amino acid–depleting drug asparaginase (138) also induce plasma FGF21 levels.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [121]
In the citing paper
“This study found that FGF21 was elevated robustly by low protein and that this induction was maximized when low-protein intake was coupled with high-carbohydrate intake (121).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [121]
In the citing paper
“Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“their data suggest that protein intake is the primary driver of circulating FGF21 levels, but that maximal FGF21 occurs in mice consuming diets that were both low in protein and high in carbohydrate”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“Both acute carbohydrate ingestion and long-term exposure to high-carbohydrate diets significantly increase liver FGF21 mRNA expression and circulating FGF21 levels”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“liver FGF21 production seems to be robustly stimulated by an imbalance in macronutrients, particularly settings of high-carbohydrate but low-protein intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“liver FGF21 expression and circulating FGF21 protein levels are increased by the restriction of protein intake in mice, rats, and humans”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“the effect of high carbohydrate and low protein to increase FGF21 appears to be regulated independently”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“This increase in FGF21 is directly related to reduced protein intake, as it occurs in settings of both low and high carbohydrate and low and high fat”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
In the citing paper
“reductions in dietary protein intake—or the intake of specific amino acids—increase liver FGF21 mRNA expression and circulating FGF21 protein levels”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [145]
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Self-citation
Metadata
- Authors
- Solon-Biet, S. M., Cogger, V. C., Pulpitel, T., Heblinski, M., Wahl, D., McMahon, A. C., Warren, A., Durrant-Whyte, J., Walters, K. A., Krycer, J. R., Ponton, F., Gokarn, R., Wali, J. A., Ruohonen, K., Conigrave, A. D., James, D. E., Raubenheimer, D., Morrison, C. D., Le Couteur, D. G., & Simpson, S. J.
- Affiliations
- The University of Sydney (AU)
- Pennington Biomedical Research Center (US)
- Corresponding author
- Simpson, Stephen J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 24
- Issue
- 4
- Pages
- 555-565
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2526341840
- Cited by
- 212
- References
- 63
- Citations by year
- 2026: 7 · 2025: 22 · 2024: 21 · 2023: 20 · 2022: 29 · 2021: 21 · 2020: 20 · 2019: 24 · 2018: 22 · 2017: 24 · 2016: 2
- FWCI
- 12.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council (NHMRC) of Australia (571328, 571408)
- Ageing and Alzheimers Institute (AAAI) of Concord Hospital
- Australian Research Council (160101119)
- National Medical Health and Research Council of Australia (1110098)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- FGF21, protein restriction, geometric framework, dietary protein, carbohydrate intake, fasting, overfeeding, hyperphagia, starvation, ketogenic diet, high-carbohydrate diet
- MeSH terms
- Uncoupling Protein 1, Animals, Animal Nutritional Physiological Phenomena, Appetite, Dietary Proteins, Energy Metabolism, Female, Fibroblast Growth Factors, Gene Expression Regulation, Glucose, Insulin-Like Growth Factor I, Male, Mice, Inbred C57BL, Models, Biological, Phenotype, Activating Transcription Factors
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