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FGF21 is an endocrine signal of protein restriction
Open accessAbstract
Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.
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In the citing paper
“ketogenic diets do not induce plasma FGF21 levels in humans26,30,34”
From Metabolic messengers: FGF21 (2021) · cites this paper as [26]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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 [146]
In the citing paper
“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 [26]
In the citing paper
“protein restriction through pathways dependent on the transcription factors ATF4 and NRF26,27.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [26]
In the citing paper
“Beyond the response to high carbohydrate, FGF21 is induced in response to protein imbalance, specifically dietary-protein dilution26,27,124.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [26]
In the citing paper
“FGF21 is required for the increases in energy expenditure and the prevention of weight gain associated with low-protein diets26,27.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [26]
In the citing paper
“This robust increase in FGF21 results in increased energy expenditure and lower body weight gain [155,156,160,163] (Figure 2)”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [155]
In the citing paper
“Elevation of circulating FGF21 levels in response to low protein levels increases both the browning of adipose tissues and energy expenditure (73), likely to offset this increased caloric intake (Figure 2).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [73]
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 [73]
In the citing paper
“FGF21 is absolutely necessary in mice to mediate the effects of low-protein diets (72, 73, 85).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [73]
In the citing paper
“Importantly, it is unclear whether there is any translational relevance of FGF21 to the beneficial effects of ketogenic diets in humans because circulating FGF21 levels fail to increase in humans in response to a ketogenic diet (19, 42, 73).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [73]
In the citing paper
“Interestingly, protein restriction promotes systemic energy expenditure through this elevation in plasma FGF21 levels (73, 85).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [73]
In the citing paper
“FGF21 is markedly induced in response to protein restriction (25, 73, 85) but not caloric restriction (73, 148).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [73]
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 [146]
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 [146]
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 [146]
In the citing paper
“Although wild-type mice exhibit changes in growth, body composition, food intake, energy expenditure, and glucose metabolism in response to dietary protein restriction, these effects are absent in mice that lack FGF21”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [146]
In the citing paper
“this increase in FGF21 is absolutely required for metabolic responses to protein restriction”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [146]
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Citations
Cites
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“29 Further studies could focus on ketone body metabolism and the impact of inhibition on it.”
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“32 In future, diet (cid:1) exercise interplay studies should also be extended to humans, as body weight is a clear determinant of weight-bearing human movement economy, 14,15,50,51 and the increase in Fgf21 7,8,43,52 and energy expenditure 43,52 with DPD is conserved in humans.”
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Inter-organ communication in physiology and pathophysiology : a role for the ChREBP-FGF21 axis?
Carbinatti, T. (2024) · theses.fr (ABES) · doi:10.70675/5d147ab4zad37z4f6bzac51z32a08efeaa51
Roisné-Hamelin, G. (2024) · theses.fr (ABES) · doi:10.70675/006069a1zb2b5z45e8zbe4fz5af5e3b6e229
Bruse, J., Marbach, C., Polizzi, A., Landré, T., Salvi, J., Alquier‐Bacquie, V., Chen, S.-P., Huillet, M., Rives, C., Céline, M., et al. (2026) · EMBO Reports · doi:10.1038/s44319-026-00790-9
“…in the liver in response to protein restriction (Laeger et al, 2014; De Sousa-Coelho et al, 2012; Nicolaisen et al, 2025; Solon-Biet et al, 2023) and acts in the brain to enhance protein appetite while suppressing sugar preference (Laeger et al, 2014, 2016; Hill et al, 2019; Talukdar et al, 2016).”
InfluentialHollstein, T., Diederich, W., Bohlmann, D., Remy, S., Ziegler, J., Hartmann, K., Kruse, L., Rohmann, N., Geisler, C., Bosy-Westphal, A., et al. (2026) · Diabetologie und Stoffwechsel · doi:10.1055/s-0046-1819887
Evidence for a protein leverage effect on food intake in a Norwegian population
Eriksen, R., Rognmo, K., Hopstock, L. A., & McCutcheon, J. E. (2026) · Appetite · doi:10.1016/j.appet.2026.108581
Ma, X., Rohani, P., & Sohouli, M. H. (2026) · Food & Function · doi:10.1039/d5fo04706d
Lyster, A. E., Frederiksen, A. S., Jensen, J. K., Lundsgaard, A., Andersen, N. M., Jørgensen, K. S., Weber, D., Nachtigall, L., Richter, E. A., Fritzen, A. M., et al. (2026) · Obesity · doi:10.1002/oby.70248 · Cited by 1
Benoit, B., Letourneau, P., Verdier, V., Viney, A., Barnel, C., Chikh, K., Vitalis, O., Jalabert, A., Wagner, S., Laiola, M., et al. (2026) · Gut Microbes · doi:10.1080/19490976.2026.2696622
“15,16,26 However, chronically elevated FGF21 levels have been associated with adverse outcomes in CKD 27 and with PEW-related conditions.”
de Luis, D., Primo, D., Izaola, O., Ovalle, H. F., & Lopez-Gomez, J. J. (2026) · Nutrición Hospitalaria · doi:10.20960/nh.07003
Dynamics of feeding behaviour and meal patterning in protein-restricted mice
Taghipourbibalan, H., & McCutcheon, J. E. (2026) · Physiology & Behavior · doi:10.1016/j.physbeh.2026.115454 · Cited by 3
Positive actions of fibroblast growth factor 21 on female zebrafish reproductive axis
Uju, C. N., & Unniappan, S. (2026) · Theriogenology · doi:10.1016/j.theriogenology.2026.118106
Calo, J., Ferreiro, D., Pérez-Tierra, G., Soengas, J. L., & Velasco, C. (2026) · Comparative biochemistry and physiology. Part A, Molecular & integrative physiology · doi:10.1016/j.cbpa.2026.112057
Carraro, V., Cherpaz, M., Longechamp, L., Coudy‐Gandilhon, C., Parry, L., Voyard, G., Maurin, A., Jousse, C., Avérous, J., Combaret, L., et al. (2026) · Journal of Molecular Biology · doi:10.1016/j.jmb.2026.169990
Protein restriction and the hallmarks of aging: A coordinated physiological adaptive response?
Kim, S. Q., Yu, S., & Morrison, C. D. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.08.005
Self-citationRevisiting gut microbiota-driven ammonia metabolism: from disease burden to physiological adaptation
Chen, H., Wang, Z., Huang, J., & Yu, Z. (2026) · Gut Microbes · doi:10.1080/19490976.2026.2722486 · Cited by 1
“111,112,145 In a defined-community mouse model, Tanoue et al. further showed that Bilophila sp. 4_1_30 and Adlercreutzia equolifaciens upregulated nrfA - related nitrogen metabolism under low-protein conditions, while Romboutsia timonensis supported coloni zation and metabolic output.”
Human brown fat metabolism associates with systemic branched-chain amino acids homeostasis
U-Din, M., Acosta, F. M., Saari, T., de Mello, V. D., van der Kolk, B. W., Monfort‐Pires, M., Clemente‐Postigo, M., Niemi, T., Taittonen, M. T., Tuomainen, M. H., et al. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102434
“BAT can also release BCAA-derived metabolites, such as 3-hydroxyisobutyrate, as well as endocrine factors like fibroblast growth factor 21 (FGF21) [35,36], which in rodents regulate muscle metabolism and contribute to amino acid homeostasis [37].”
Sexual dimorphisms in juvenile development under nutritionnal stress
Joly, A., & Leulier, F. (2026) · Comptes Rendus Biologies · doi:10.5802/crbiol.203
Jóhönnuson, E. M. S., Reiche, J., Richter, M. M., & Albrechtsen, N. J. W. (2026) · Endocrine Connections · doi:10.1530/ec-26-0537
“Hepatic nutrient-sensing mediators, such as FGF21, have been implicated in endocrine adaptation to altered protein availability (15, 16, 17), although these pathways were not assessed in the present study.”
The role of curcumin in regulating hepatokine-mediated metabolic processes
Ghoflchi, S., Aliyari, M., Hosseini, H., Kesharwani, P., & Sahebkar, A. (2026) · PharmaNutrition · doi:10.1016/j.phanu.2026.100526
Alcohol, but not acetate, induces FGF21 in humans without association with subsequent food choice
Ramne, S., Dragsted, L. O., Dinjens, V., Magkos, F., Gillum, M. P., & Cuparencu, C. (2026) · The Journal of Nutritional Physiology · doi:10.1016/j.jnphys.2026.100048
Sumioki, H., Tomatsu, E., Seino, Y., Hidaka, S., Ueno, S., Kanie, S., Nishida, K., Haraguchi, T., Murao, N., Fujisawa, H., et al. (2026) · Physiological Reports · doi:10.14814/phy2.71117
“Despite evidence that chronic protein and sucrose intake modulate FGF21 in rodents (Laeger et al., 2014; Maekawa et al., 2017), the effects of acute administration remain largely unexplored.”
Leenders, L. M., Casagranda, S., Balvers, M. G. J., de Gier, G., Lambers, T. T., & Smeets, P. A. M. (2026) · medRxiv · doi:10.64898/2026.09.23.26363226
Lucaciu, R. L., Hangan, A. C., & Procopciuc, L. M. (2026) · Nutrients · doi:10.3390/nu18203382
“ATF4 also links cellular amino acid sensing to systemic metabolic adaptation by stimulating hepatic FGF21 expression during dietary amino acid or protein restriction [7,38].”
Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging
Salmón‐Gómez, L., Keipert, S., Catalán, V., Rodrı́guez, A., Becerril, S., Frühbeck, G., & Gómez‐Ambrosi, J. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00627-w
“Notably, the rise in FGF21 concentrations induced by protein restriction is required for several metabolic benefits, including increased energy expenditure, reduced weight gain and improved glucose homeostasis in DIO mice, as these effects are blunted in mice lacking Fgf21 [60].”
Metadata
- Authors
- 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., & Morrison, C. D.
- Affiliations
- Pennington Biomedical Research Center (US)
- Virginia Tech (US)
- University of Washington (US)
- Corresponding author
- Morrison, Christopher D.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-08-18
- Volume
- 124
- Issue
- 9
- Pages
- 3913-3922
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4153701
- OpenAlex
- W2170065584
- Cited by
- 593
- References
- 59
- Citations by year
- 2026: 42 · 2025: 58 · 2024: 47 · 2023: 48 · 2022: 58 · 2021: 54 · 2020: 43 · 2019: 51 · 2018: 46 · 2017: 56 · 2016: 51 · 2015: 34 · 2014: 4
- FWCI
- 19.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (LA 3042/2-1)
- National Institutes of Health
- Nutrition Obesity Research Center, University of North Carolina (#P30DK072476)
- National Institute of General Medical Sciences (P20GM103528, P30GM118430)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101997, R01DK096311, R01DK081563, P30DK035816, P30DK017047, T32DK064584, P30DK072476, R01DK083042)
- National Center for Research Resources (P20RR021945)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- FGF21, protein restriction, low-protein diet, hormone signaling, eIF2α phosphorylation, GCN2, starvation, ketogenic diet, dietary intake, energy expenditure, body weight, metabolic adaptation
- MeSH terms
- Animals, Dietary Proteins, Energy Metabolism, Fibroblast Growth Factors, Male, Mice, Inbred C57BL, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Caloric Restriction, PPAR alpha, Mice, Rats, Diet, Ketogenic
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