FGF21 Regulates Sweet and Alcohol Preference
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a hormone induced by various metabolic stresses, including ketogenic and high-carbohydrate diets, that regulates energy homeostasis. In humans, SNPs in and around the FGF21 gene have been associated with macronutrient preference, including carbohydrate, fat, and protein intake. Here we show that FGF21 administration markedly reduces sweet and alcohol preference in mice and sweet preference in cynomolgus monkeys. In mice, these effects require the FGF21 co-receptor β-Klotho in the central nervous system and correlate with reductions in dopamine concentrations in the nucleus accumbens. Since analogs of FGF21 are currently undergoing clinical evaluation for the treatment of obesity and type 2 diabetes, our findings raise the possibility that FGF21 administration could affect nutrient preference and other reward behaviors in humans.
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Administration of FGF21 suppresses alcohol intake.
“Similarly to its regulation of nutrient homeostasis, FGF21 production by the liver is also increased in response to alcohol intake132,133, and administration of FGF21 suppresses alcohol intake122,134.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [122]
FGF21 signals to the CNS and suppresses simple-sugar intake and sweet-taste preference, but not protein or lipid intake.
“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 [122]
Pharmacological administration of FGF21 decreases sugar and alcohol intake in mice.
“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 [138]
Hepatic FGF21 increases in response to nutritional stimuli including macronutrient imbalance and alcohol intake.
“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 [138]
Excess simple sugar intake increases plasma FGF21 levels in humans and rodents.
“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 [138]
FGF21 regulates sweet taste preference in primates and humans.
“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 [125]
FGF21 suppresses the intake of noncaloric sweeteners.
“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 [125]
Administering recombinant FGF21 or overexpressing FGF21 significantly reduced alcohol preference but not plasma ethanol concentrations.
“Interestingly, administering recombinant FGF21 (116) or the overexpression of FGF21 (125) significantly reduced alcohol preference but not plasma ethanol concentrations.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [125]
When an FGF21 analog, PF-05231023, was administered to monkeys, they rapidly and significantly reduced their saccharin intake.
“When an FGF21 analog, PF-05231023, was administered to monkeys, they rapidly and significantly reduced their saccharin intake (125).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [125]
FGF21 administration increases total fluid intake through increased water intake in the presence of alcohol.
“While FGF21 decreases alcohol intake, it should be noted that the effect on alcohol preference is impacted by the fact that FGF21 administration also increases total fluid intake through increased water intake in the presence of alcohol (125).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [125]
Exogenous FGF21 treatment reduces the consumption of sweet foods and alcohol while alternatively increasing the consumption of protein.
“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 [179]
The inhibition of saccharin was reproduced in monkeys treated with an FGF21 analog.
“the inhibition of saccharin was reproduced in monkeys treated with an FGF21 analog”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [179]
FGF21 acts in the brain, via Klb, to suppress sweet and alcohol intake.
“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 [179]
The effect of FGF21 on sweet intake could be reproduced by exogenous FGF21 administration in control mice, but not mice lacking Klb in the brain.
“This effect on sweet intake could be reproduced by exogenous FGF21 administration in control mice, but not mice lacking Klb in the brain.”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [179]
Transgenic FGF21 overexpression reduced sucrose, saccharin, and alcohol intake.
“transgenic FGF21 overexpression reduced sucrose, saccharin, and alcohol intake”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [179]
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- Authors
- Talukdar, S., Owen, B. M., Song, P., Hernandez, G., Zhang, Y., Zhou, Y., Scott, W. T., Paratala, B., Turner, T., Smith, A., Bernardo, B., Müller, C. P., Tang, H., Mangelsdorf, D. J., Goodwin, B., & Kliewer, S. A.
- Affiliations
- Pfizer (United States) (US)
- The University of Texas Southwestern Medical Center (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mangelsdorf, David J.
- Kliewer, Steven A.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 23
- Issue
- 2
- Pages
- 344-349
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4749404
- OpenAlex
- W2198244887
- Cited by
- 342
- References
- 31
- Citations by year
- 2026: 25 · 2025: 31 · 2024: 24 · 2023: 30 · 2022: 44 · 2021: 36 · 2020: 44 · 2019: 27 · 2018: 28 · 2017: 30 · 2016: 23
- FWCI
- 11.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Welch Foundation (I-1275, I-1558)
- Wellcome Trust
- Royal Society (105545/Z/14/Z)
- National Institutes of Health (5P50 CA70907-16, NNX11AC54G, R01CA152301, R01DK067158)
- Deutsche Forschungsgemeinschaft (MU 2789/8-1)
- Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
- Howard Hughes Medical Institute
- Ford Foundation
- 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, sweet taste preference, alcohol preference, macronutrient preference, β-Klotho, dopamine, nucleus accumbens, reward behavior, energy homeostasis, obesity, type 2 diabetes, FGF21 analogs
- MeSH terms
- Alcohols, Animals, Haplorhini, Central Nervous System, Dopamine, Fibroblast Growth Factors, Food Preferences, Humans, Male, Mice, Inbred C57BL, Saccharin, Taste, Signal Transduction
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