Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates
Open accessAbstract
Objective Fibroblast-growth factor 21 (FGF21) is thought to be important in metabolic regulation. Recently, low protein diets have been shown to increase circulating FGF21 levels. However, when energy contribution from dietary protein is lowered, other macronutrients, such as carbohydrates, must be increased to meet eucaloric balance. This raises the possibility that intake of a diet rich in carbohydrates may induce an increase in plasma FGF21 levels per se. Here we studied the role of dietary carbohydrates on the levels of circulating FGF21 and concomitant physiologic effects by feeding healthy men a carbohydrate rich diet without reducing protein intake. Methods A diet enriched in carbohydrates (80 E% carbohydrate; CHO) and a eucaloric control diet (CON) were provided to nine healthy men for three days. The energy intake during the CHO diet was increased (+75% energy) to ensure similar dietary protein intake in CHO and CON. To control for the effect of caloric surplus, we similarly overfed (+75% energy) the same subjects for three days with a fat-rich diet (78 E% fat; FAT), consisting of primarily unsaturated fatty acids. The three diets were provided in random order. Results After CHO, plasma FGF21 concentration increased 8-fold compared to CON (329 ± 99 vs. 39 ± 9 pg ml −1 , p < 0.05). In contrast, after FAT only a non-significant tendency (p = 0.073) to an increase in plasma FGF21 concentration was found. The increase in FGF21 concentration after CHO correlated closely (r = 0.88, p < 0.01) with increased leg glucose uptake (62%, p < 0.05) and increased hepatic glucose production (17%, p < 0.01), indicating increased glucose turnover. Plasma fatty acid (FA) concentration was decreased by 68% (p < 0.01), supported by reduced subcutaneous adipose tissue HSL Ser 660 phosphorylation (p < 0.01) and perilipin 1 protein content (p < 0.01), pointing to a suppression of adipose tissue lipolysis. Concomitantly, a 146% increase in the plasma marker of hepatic de novo lipogenesis C16:1 n−7 FA (p < 0.01) was observed together with 101% increased plasma TG concentration (p < 0.001) in association with CHO intake and increased plasma FGF21 concentration. Conclusion Excess dietary carbohydrate, but not fat, led to markedly increased FGF21 secretion in humans, notably without protein restriction, and affected glucose and lipid homeostais.
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Starvation, high sugar intake, and dietary protein restriction all induce circulating FGF21 levels in humans.
“Starvation30,31, high sugar intake32,33 and dietary protein restriction26 all induce circulating FGF21 levels in humans.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [33]
FGF21 is induced by simple-sugar intake in both mice and humans, and sugar-induced production of FGF21 from the liver occurs in a ChREBP-dependent manner.
“FGF21 is induced by simple-sugar intake in both mice and humans22,32,33, and that sugar-induced production of FGF21 from the liver occurs in a ChREBP-dependent manner22,121.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [33]
Plasma FGF21 levels are induced by increases in both glucose and insulin levels in humans.
“In addition, in humans, plasma FGF21 levels have been shown to be induced by increases in both glucose and insulin levels (31, 84, 110, 133), supporting a role during refeeding.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [84]
Excess carbohydrate without affecting protein levels led to an approximately eightfold increase in circulating FGF21 levels, an effect not observed with increased fat intake.
“Notably, without affecting protein levels, excess carbohydrate led to an approximately eightfold increase in circulating FGF21 levels, an effect not observed with increased fat intake (84).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [84]
Circulating FGF21 levels are robustly increased by diets that are high in carbohydrate but low in protein.
“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 [143]
The effect of high carbohydrate and low protein to increase FGF21 appears to be regulated independently.
“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 [143]
Both acute carbohydrate ingestion and long-term exposure to high-carbohydrate diets significantly increase liver FGF21 mRNA expression and circulating FGF21 levels.
“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 [143]
Liver FGF21 production is robustly stimulated by an imbalance in macronutrients, particularly settings of high-carbohydrate but low-protein intake.
“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 [143]
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- Authors
- Lundsgaard, A.-M., Fritzen, A. M., Sjøberg, K. A., Myrmel, L. S., Madsen, L., Wojtaszewski, J. F. P., Richter, E. A., & Kiens, B.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Kiens, Bente
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 6
- Issue
- 1
- Pages
- 22-29
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5220397
- OpenAlex
- W2557128275
- Cited by
- 126
- References
- 56
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 14 · 2023: 12 · 2022: 18 · 2021: 16 · 2020: 10 · 2019: 18 · 2018: 11 · 2017: 11
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Københavns Universitet
- Novo Nordisk Fonden
- Sundhed og Sygdom, Det Frie Forskningsråd
- Danish Diabetes Academy
- Ministeriet for Fø devarer, Landbrug og Fiskeri (3304-FSE-06-0510)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- FGF21, dietary carbohydrates, energy surplus, high-fat diet, hepatic glucose production, hepatic de novo lipogenesis, adipose tissue lipolysis, hormone-sensitive lipase, PLIN1, plasma fatty acids, metabolic regulation, low-protein diet, healthy men, short-term dietary intervention, unsaturated fatty acids
- MeSH terms
- Adult, Energy Intake, Dietary Carbohydrates, Dietary Fats, Dietary Proteins, Energy Metabolism, Fibroblast Growth Factors, Glucose, Humans, Insulin, Liver, Male, Lipogenesis
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