The DOI matches its Crossref record; 36 of the 37 references it cites were found in a registry or an index.
FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver
Open accessAbstract
The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of "sweets."
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In the citing paper
“Finally, increased levels of the hepatokine FGF21, although not influencing appetite per se, have been linked to decreased intake of obesogenic sugary foods [168] (5).”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [168]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [133]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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 [144]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Interestingly, a recent study suggests that FGF21 may be involved in regulating preference for specific foods; specifically, it acts to reduce craving for sugary foods [168].”
In the citing paper
“Hepatic mRNA and plasma protein levels of FGF21 are induced by high sugar intake through a mechanism dependent on the transcription factor ChREBP22–25”
From Metabolic messengers: FGF21 (2021) · cites this paper as [22]
In the citing paper
“KLB expression is primarily restricted to specific metabolic tissues (for example, the liver, pancreas and adipose tissue)5, and lower expression is observed in the brain22,48–50. Despite some reports to the contrary51,52, KLB is not expressed in muscle5,41.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [22]
In the citing paper
“mice lacking FGF21 also exhibit a greater preference for sucrose22.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [22]
In the citing paper
“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 [22]
In the citing paper
“FGF21 signals to the CNS and consequently suppresses simple-sugar intake and sweet-taste preference22,122, but not protein or lipid intake22,84.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [22]
In the citing paper
“Thus, increased FGF21 production from the liver in response to carbohydrate intake is a negative feedback loop regulating carbohydrate intake22.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [22]
In the citing paper
“While physiological FGF21 signalling to glutamatergic neurons in the paraventricular nucleus regulates basal sucrose intake22,48, FGF21 signalling to glutamatergic neurons in the ventromedial hypothalamus (VMH) is required for FGF21-mediated suppression of simple-sugar intake48.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [22]
In the citing paper
“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [137]
In the citing paper
“Excess simple sugar intake increases plasma FGF21 levels in humans and rodents [137,138].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [137]
In the citing paper
“FGF21 also regulates macronutrient-specific intake and sweet-taste preference in response to the activation of the hepatic glucose-sensitive transcription factor, carbohydrate responsive element-binding protein (ChREBP) [137].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [137]
In the citing paper
“Consistent with these data in humans, Fgf21 total knockout mice exhibit an increased preference for simple sugars, but not lipids or protein (133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
In the citing paper
“Indeed, the administration of recombinant FGF21 to mice markedly reduces carbohydrate preference without affecting the preferences for lipid and protein (133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
In the citing paper
“Interestingly, FGF21 also suppresses the intake of noncaloric sweeteners (125, 133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
In the citing paper
“Importantly, loss of β-klotho in the PVN of the hypothalamus, but not the suprachiasmatic nucleus, impaired FGF21-mediated suppression of sucrose intake (133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
In the citing paper
“Mice lacking ChREBP fail to show an increase in plasma FGF21 levels in response to simple sugar intake (35, 133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
In the citing paper
“Ad libitum feeding of sucrose for 6–24 hours gradually increases hepatic and plasma FGF21 levels in wild-type mice, and this effect is lost in liver-specific Fgf21 knockout mice (133).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
In the citing paper
“FGF21 mediates these effects on simple sugar and sweet taste preference not by affecting sweet taste sensing, but rather by affecting taste processing.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [133]
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 [144]
In the citing paper
“exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
In the citing paper
“driven at least in part by the transcription factor carbohydrate response element binding protein (ChREBP), which binds directly to the FGF21 promoter”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
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 [144]
In the citing paper
“FGF21 acts in the brain, via Klb, to suppress sweet and alcohol intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
In the citing paper
“The best evidence currently supports the hypothalamic PVN, as the deletion of Klb from the PVN blocked the effects on sweet intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
In the citing paper
“This effect of FGF21 on sweet intake was impaired when the FGF21 co-receptor Klb was deleted from the hypothalamic paraventricular nucleus (PVN).”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
In the citing paper
“these FGF21-dependent effects appeared to be specific for sweet/sugar, as there was no effect on the nonsweet carbohydrate maltodextrin”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
In the citing paper
“mice that genetically overexpressed or were treated with FGF21 reduced their consumption of a high-sucrose diet and reduced their consumption of sucrose and the noncaloric sweeteners saccharin and sucralose”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
In the citing paper
“FGF21-deficient mice increased their consumption of a solid, high-sucrose diet, as well as solutions containing sucrose, glucose, or fructose”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [144]
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Citations
Cites
Mammalian sweet taste receptors
Nelson, G., Hoon, M. A., Chandrashekar, J., Zhang, Y., Ryba, N. J. P., & Zuker, C. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00451-2 · Cited by 1,702
Inagaki, T., Dutchak, P., Zhao, G., Ding, X., Gautron, L., Parameswara, V., Li, Y., Goetz, R., Mohammadi, M., Esser, V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.003 · Cited by 1,504
Johnson, R. K., Appel, L. J., Brands, M., Howard, B. V., Lefevre, M., Lustig, R. H., Sacks, F., Steffen, L. M., & Wylie-Rosett, J. (2009) · Circulation · doi:10.1161/circulationaha.109.192627 · Cited by 1,207
Imamura, F., O’Connor, L., Ye, Z., Mursu, J., Hayashino, Y., Bhupathiraju, S. N., & Forouhi, N. G. (2015) · BMJ · doi:10.1136/bmj.h3576 · Cited by 977 · cited 3×
“has been linked with metabolic disease (Imamura et al., 2015; Johnson et al., 2009).”
Imamura, F., O’Connor, L., Ye, Z., Mursu, J., Hayashino, Y., Bhupathiraju, S. N., & Forouhi, N. G. (2016) · British Journal of Sports Medicine · doi:10.1136/bjsports-2016-h3576rep · Cited by 968
Iizuka, K., Bruick, R. K., Liang, G., Horton, J. D., & Uyeda, K. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401516101 · Cited by 834
Potthoff, M. J., Inagaki, T., Satapati, S., Ding, X., He, T., Goetz, R., Mohammadi, M., Finck, B. N., Mangelsdorf, D. J., Kliewer, S. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904187106 · Cited by 704
Self-citationDetection of Sweet and Umami Taste in the Absence of Taste Receptor T1r3
Damak, S., Rong, M., Yasumatsu, K., Kokrashvili, Z., Varadarajan, V., Zou, S., Jiang, P., Ninomiya, Y., & Margolskee, R. F. (2003) · Science · doi:10.1126/science.1087155 · Cited by 632
FGF21 is an endocrine signal of protein restriction
Laeger, T., Henagan, T. M., Albarado, D. C., Redman, L. M., Bray, G. A., Noland, R. C., Münzberg, H., Hutson, S. M., Gettys, T. W., Schwartz, M. W., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74915 · Cited by 593 · cited 1×
“Interestingly, consumption of low protein diets also increases hepatic and plasma FGF21 levels in humans (Laeger et al., 2014).”
Circulating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding
Markan, K. R., Naber, M. C., Ameka, M. K., Anderegg, M. D., Mangelsdorf, D. J., Kliewer, S. A., Mohammadi, M., & Potthoff, M. J. (2014) · Diabetes · doi:10.2337/db14-0595 · Cited by 590
Self-citation
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Metabolism disrupting chemicals and metabolic disorders
Heindel, J. J., Blumberg, B., Cave, M., Machtinger, R., Mantovani, A., Mendez, M. A., Nadal, A., Palanza, P., Panzica, G., Sargis, R., et al. (2017) · Reproductive Toxicology · doi:10.1016/j.reprotox.2016.10.001 · Cited by 1,101
Physical activity and muscle-brain crosstalk
Pedersen, B. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0174-x · Cited by 772
Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine
Fujiwara, N., Friedman, S. L., Goossens, N., & Hoshida, Y. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.016 · Cited by 659
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607
Fructose metabolism and metabolic disease
Hannou, S. A., Haslam, D. E., McKeown, N. M., & Herman, M. A. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96702 · Cited by 561
Metadata
- Authors
- von Holstein-Rathlou, S., BonDurant, L. D., Peltekian, L., Naber, M. C., Yin, T. C., Claflin, K. E., Urizar, A. I., Madsen, A. N., Ratner, C., Holst, B., Karstoft, K., Vandenbeuch, A., Anderson, C. B., Cassell, M. D., Thompson, A. P., Solomon, T. P., Rahmouni, K., Kinnamon, S. C., Pieper, A. A., Gillum, M. P., & Potthoff, M. J.
- Affiliations
- University of Iowa (US)
- University of Copenhagen (DK)
- Rigshospitalet (DK)
- University of Colorado Anschutz (US)
- Corresponding author
- Gillum, Matthew P.
- Potthoff, Matthew J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 23
- Issue
- 2
- Pages
- 335-343
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4756759
- OpenAlex
- W2201894846
- Cited by
- 347
- References
- 37
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 33 · 2023: 22 · 2022: 43 · 2021: 42 · 2020: 40 · 2019: 33 · 2018: 29 · 2017: 38 · 2016: 24
- FWCI
- 13.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Novo Nordisk Fonden (NNF14OC0009525, NNF15SA0018486)
- National Heart, Lung, and Blood Institute (P01HL084207)
- National Institute on Deafness and Other Communication Disorders (P30DC004657)
- National Institute of General Medical Sciences (T32GM067795)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106104)
- 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, carbohydrate intake, sucrose intake, sweet taste preference, artificial sweeteners, hypothalamic neurons, meal size, liver-brain axis, macronutrient preference, negative feedback loop
- MeSH terms
- Animals, Endocrine System, Feeding Behavior, Fibroblast Growth Factors, Food Preferences, Liver, Male, Nuclear Proteins, Sucrose, Taste, Transcription Factors, Signal Transduction, Mice, Knockout, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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