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FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
Open accessAbstract
The liking and selective ingestion of palatable foods-including sweets-is biologically controlled, and dysfunction of this regulation may promote unhealthy eating, obesity, and disease. The hepatokine fibroblast growth factor 21 (FGF21) reduces sweet consumption in rodents and primates, whereas knockout of Fgf21 increases sugar consumption in mice. To investigate the relevance of these findings in humans, we genotyped variants in the FGF21 locus in participants from the Danish Inter99 cohort (n = 6,514) and examined their relationship with a detailed range of food and ingestive behaviors. This revealed statistically significant associations between FGF21 rs838133 and increased consumption of candy, as well as nominal associations with increased alcohol intake and daily smoking. Moreover, in a separate clinical study, plasma FGF21 levels increased acutely after oral sucrose ingestion and were elevated in fasted sweet-disliking individuals. These data suggest the liver may secrete hormones that influence eating behavior.
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In the citing paper
“These single-nucleotide polymorphisms are also associated with increases in sweet-taste preference119 and greater waist-to-hip ratios120.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [119]
In the citing paper
“Although variants around the FGF21 locus are associated with changes in macronutrient intake, they are not associated with obesity or type 2 diabetes (120).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [120]
In the citing paper
“As was observed with increased carbohydrate intake (20, 127), statistically significant associations were identified between the FGF21 rs838133 allele and increased candy consumption (120).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [120]
In the citing paper
“FGF21 also regulates sweet taste preference in primates and humans.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [120]
In the citing paper
“A third report also identified SNPs at the FGF21 locus associating with a preference for sweets (120).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [120]
In the citing paper
“another nutritional intervention was shown to robustly increase FGF21: alcohol consumption. Ample evidence, in both rodents and humans, demonstrates that ethanol intake increases FGF21 production, largely by the liver”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [166]
In the citing paper
“Additional studies have since supported this relationship between FGF21 and macronutrient intake, including associations with alcohol intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [166]
In the citing paper
“FGF21 sequence variants are linked with alterations in macronutrient preference and alcohol intake in humans”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [166]
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ResultInfluentialFGF21 suppresses alcohol consumption through an amygdalo-striatal circuit
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“Since then, the observation that sucrose, the most abundant dietary sugar, induces FGF21 expression has been expanded to include humans (Søberg et al. 2017), and a relationship with the FGF21 pathway has also been documented for alcohol intake (Schumann et al. 2016; Talukdar et al. 2016; Frayling…”
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Fibroblast growth factor 21 is a hepatokine involved in MASLD progression
Gallego‐Durán, R., Ampuero, J., Maya‐Miles, D., Pastor‐Ramírez, H., Montero‐Vallejo, R., Rivera‐Esteban, J., Álvarez‐Amor, L., Pareja, M. J., Rico, M. C., Millán, R., et al. (2024) · United European Gastroenterology Journal · doi:10.1002/ueg2.12534 · Cited by 35
“34 Besides, the A ‐ allele has been strongly associated with higher blood pressure and waist ‐ hip ratio, despite an association with lower total body ‐ fat percentage, 10 as well as linked to high salt intake.”
BackgroundNew Horizon: Exercise and a Focus on Tissue-Brain Crosstalk
Townsend, L. K., MacPherson, R. E. K., & Wright, D. C. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab333 · Cited by 36
FGF21 increases water intake, urine output and blood pressure in rats
Turner, T., Chen, X., Zahner, M. R., Opsahl, A., DeMarco, G. J., Boucher, M., Goodwin, B. J., & Perreault, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0202182 · Cited by 33
PGC1α Controls Sucrose Taste Sensitization in Drosophila
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Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis
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Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?
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Fibroblast growth factor 21 as a potential master regulator in metabolic disorders
Velingkar, A., Vuree, S., Prabhakar, P. K., Kalashikam, R. R., Banerjee, A., & Kondeti, S. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00244.2022 · Cited by 32
Roux-en-Y Gastric Bypass Surgery Has Unique Effects on Postprandial FGF21 but Not FGF19 Secretion
Harris, L.-A. L. S., Smith, G. I., Mittendorfer, B., Eagon, J. C., Okunade, A. L., Patterson, B. W., & Klein, S. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01295 · Cited by 32
Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases
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Dietary Patterns and Their Associations With the FTO and FGF21 Gene Variants Among Emirati Adults
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“Genotyping was performed for FTOrs9939609(A>T), rs9930506(A>G), FGF21 rs838133 (A > G), and FGF21 rs838145 (A>G) as previously described (30, 31).”
BackgroundMethodNutrition for precision health: The time is now
Qi, L. (2022) · Obesity · doi:10.1002/oby.23448 · Cited by 29
Gluco-metabolic effects of oral and intravenous alcohol administration in men
Lanng, A. R., Gasbjerg, L. S., Bergmann, N. C., Bergmann, S., Helsted, M. M., Gillum, M. P., Hartmann, B., Holst, J. J., Vilsbøll, T., & Knop, F. K. (2019) · Endocrine Connections · doi:10.1530/ec-19-0317 · Cited by 30
Self-citationConverging vulnerability factors for compulsive food and drug use
Serafine, K. M., O’Dell, L. E., & Zorrilla, E. P. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108556 · Cited by 29
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FGF21 impedes peripheral myelin development by stimulating p38 MAPK/c‐Jun axis
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“FGF21 also influences eating behavior, that is, FGF21 reduces sweet consumption in humans and rodents (Soberg et al., 2017).”
BackgroundFerrer‐Curriu, G., Guitart‐Mampel, M., Rupérez, C., Zamora, M., Crispi, F., Villarroya, F., Fernández‐Solà, J., Garrabou, G., & Planavila, A. (2020) · The Journal of Pathology · doi:10.1002/path.5573 · Cited by 26
“In humans, KLB genetic variants are associated with increased alcohol intake [21,22].”
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“These results suggest that the glucose/fructose-ChREBP-FGF21 pathway forms a negative feedback loop regulating sugar-eating behavior [99].”
BackgroundFibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior
Wu, C.-T., CHAFFIN, A. T. B., & Ryan, K. K. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030580 · Cited by 24
“Further analyses showed that rs838133 carriers were specifically associated with high intake of sweet foods [66].”
BackgroundResultLarsen, E. L., Poulsen, H. E., Michaelsen, C., Kjær, L. K., Lyngbæk, M. P. P., Andersen, E. S., Petersen-Bønding, C., Lemoine, C., Gillum, M. P., Jørgensen, N. R., et al. (2020) · Journal of Sports Sciences · doi:10.1080/02640414.2020.1770918 · Cited by 25
“Additionally, FGF21 seems to be associated with sweet and alcohol preferences (Søberg et al., 2018, 2017).”
BackgroundSelf-citationEndocrine Fibroblast Growth Factors in Relation to Stress Signaling
Shimizu, M., & Sato, R. (2022) · Cells · doi:10.3390/cells11030505 · Cited by 25
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“In humans, excess dietary carbohydrate intake (80% of energy, with a glucose:fructose ratio of 1:1) for 3 d resulted in an 8-fold increase in FGF-21 concentrations compared with a control diet (71), whereas ingestion of 75 g sucrose doubled FGF-21 concentrations in healthy subjects, with peak responses occurring 120 m…”
Fibroblast growth factor 21: A “rheostat” for metabolic regulation?
She, Q.-Y., Bao, J., Wang, H.-Z., Liang, H., Huang, W., Wu, J., Zhong, Y.-W., Ling, H., Li, A., & Qin, S.-L. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155166 · Cited by 22
Relationship between FGF21 and drug or nondrug therapy of type 2 diabetes mellitus
Guo, C. Y., Zhao, L., Li, Y., Deng, X., & Yuan, G. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29879 · Cited by 21
“The study found that after 12 hr of fasting to exclude the effects of acute high glucose stimulation, the circulating FGF21 level of sub- jects who did not like sweet food was 51% higher than that of those who liked sweet food (Søberg et al., 2017).”
BackgroundMetabolic-Associated Fatty Liver Disease and Insulin Resistance: A Review of Complex Interlinks
Barber, T. M., Kabisch, S., Pfeiffer, A. F. H., & Weickert, M. O. (2023) · Metabolites · doi:10.3390/metabo13060757 · Cited by 22
“Data from a wide range of settings (including rodent, primate, and human-based data) show that FGF21 may reduce the consumption of sweet foods [59].”
BackgroundMetabolic Factors Determining the Susceptibility to Weight Gain: Current Evidence
Hollstein, T., & Piaggi, P. (2020) · Current Obesity Reports · doi:10.1007/s13679-020-00371-4 · Cited by 24
“Similarly, in humans, FGF21 was shown to increase energy expenditure [120] and modulate food preference [121].”
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Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency
Tiwari, V., Jin, B., Sun, O., Gonzalez, E. D. J. L., Chen, M.-H., Wu, X., Shah, H., Zhang, A., Herman, M. A., Spracklen, C. N., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01399-3 · Cited by 20
Meal sugar-protein balance determines postprandial FGF21 response in humans
Ramne, S., Duizer, L., Nielsen, M. S., Jørgensen, N. R., Svenningsen, J. S., Grarup, N., Sjödin, A. M., Raben, A., & Gillum, M. P. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00241.2023 · Cited by 20
Self-citation
Metadata
- Authors
- Søberg, S., Sandholt, C. H., Jespersen, N. Z., Toft, U., Madsen, A. L., von Holstein-Rathlou, S., Grevengoed, T. J., Christensen, K. B., Bredie, W. L. P., Potthoff, M. J., Solomon, T. P. J., Scheele, C., Linneberg, A., Jørgensen, T., Pedersen, O., Hansen, T., Gillum, M. P., & Grarup, N.
- Affiliations
- University of Copenhagen (DK)
- Capital Region of Denmark (DK)
- University of Iowa (US)
- University of Birmingham (GB)
- Corresponding author
- Gillum, Matthew P.
- Grarup, Niels
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 25
- Issue
- 5
- Pages
- 1045-1053.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2611671707
- Cited by
- 216
- References
- 66
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 18 · 2023: 20 · 2022: 25 · 2021: 33 · 2020: 33 · 2019: 23 · 2018: 19 · 2017: 13
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Funders
- TrygFonden
- Novo Nordisk Fonden (NNF15CC0018486)
- Novo Nordisk Foundation Center for Basic Metabolic Research
- Strategiske Forskningsråd (09 – 067009, 09 – 075724)
- Danmarks Frie Forskningsfond (4092-00240B)
- Danmarks Grundforskningsfond (DNRF55)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- FGF21, hepatokines, sugar consumption, sweet taste preference, food liking, sucrose intake, alcohol consumption, smoking, genetic variants, dietary habits, obesity, liver hormone
- MeSH terms
- Sugars, Adult, Appetite, Appetite Regulation, Candy, Female, Fibroblast Growth Factors, Food Preferences, Genotype, Humans, Male, Obesity, Polymorphism, Genetic, Taste, Cohort Studies, Young Adult
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