The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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
“ketogenic diets do not induce plasma FGF21 levels in humans26,30,34”
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
“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
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125
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
Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478
Coping with stress: eIF2 kinases and translational control
Wek, R. C., Jiang, H.-Y., & Anthony, T. G. (2005) · Biochemical Society Transactions · doi:10.1042/bst0340007 · Cited by 1,353
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031
Levine, M. E., Suarez, J. A., Brandhorst, S., Balasubramanian, P., Cheng, C.-W., Madia, F., Fontana, L., Mirisola, M. G., Guevara-Aguirre, J., Wan, J., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.02.006 · Cited by 910
Zhang, X., Yeung, D. C. Y., Karpisek, M., Stejskal, D., Zhou, Z.-G., Liu, F., Wong, R. L. C., Chow, W.-S., Tso, A. W. K., Lam, K. S. L., et al. (2008) · Diabetes · doi:10.2337/db07-1476 · Cited by 908
Solon-Biet, S. M., McMahon, A. C., Ballard, J. W. O., Ruohonen, K., Wu, L. E., Cogger, V. C., Warren, A., Huang, X., Pichaud, N., Melvin, R. G., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.02.009 · Cited by 904
Flagged first, then by citations
Cited by
Sorted by citations
Items 301–400 of 590
McCarty, M. F., & Lerner, A. (2020) · Advances in Nutrition · doi:10.1093/advances/nmaa112 · Cited by 19
“Protein-restricted diets in humans have likewise been shown to increase plasma FGF21 and decrease plasma insulin-like growth factor (IGF-I) (49, 51).”
BackgroundInfluentialRegulation of diurnal energy balance by mitokines
Klaus, S., Gil, C. I., & Ost, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03748-9 · Cited by 19
Postprandial dynamics and response of fibroblast growth factor 21 in older adults
Herpich, C., Haß, U., Kochlik, B., Franz, K., Laeger, T., Klaus, S., Bosy‐Westphal, A., & Norman, K. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.04.037 · Cited by 17
Self-citationMoro, J., Chaumontet, C., Even, P. C., Blais, A., Piedcoq, J., Gaudichon, C., Tomé, D., & Azzout‐Marniche, D. (2021) · Scientific Reports · doi:10.1038/s41598-021-91274-4 · Cited by 17
Malhotra, R., Cavanaugh, K. L., Blot, W. J., Ikizler, T. A., Lipworth, L. P., & Kabagambe, E. K. (2016) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2016.07.009 · Cited by 17
“High protein diet may further lead to downregulation of fibroblast growth factor 21 (FGF-21) resulting in alteration of insulin sensitivity and metabolic responses especially in blacks [47].”
BackgroundProtein-Restricted Diets and Their Impact on Metabolic Health and Aging
Kim, S. Q., Spann, R. A., Hill, C. M., Berryman, C. E., Berthoud, H., McDougal, D. H., He, Y., Münzberg, H., Yu, S., & Morrison, C. D. (2025) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-121624-114918 · Cited by 17
Self-citationDietary restriction in aging and longevity
Schmauck‐Medina, T., Lautrup, S., Francesco, A. D., Mitchell, S. J., Clemmensen, C., Partridge, L., Roth, G. S., Anderson, R. M., Mattison, J. A., de Cabo, R., et al. (2026) · Nature Aging · doi:10.1038/s43587-026-01091-5 · Cited by 18
Multiomics assessment of dietary protein titration reveals altered hepatic glucose utilization
MacArthur, M. R., Mitchell, S. J., Chadaideh, K. S., Trevino-Villarreal, J. H., Jung, J., Kalafut, K. C., Reynolds, J. S., Mann, C. G., Trocha, K. M., Tao, M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111187 · Cited by 16
Kirby, M. A., Lauer, J. M., Muhihi, A. J., Ulenga, N. K., Aboud, S., Liu, E., Choy, R. K. M., Arndt, M. B., Kou, J., Gewirtz, A. T., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104257 · Cited by 16
Hepatic interoception in health and disease
Berthoud, H., Münzberg, H., Morrison, C. D., & Neuhuber, W. (2024) · Autonomic Neuroscience · doi:10.1016/j.autneu.2024.103174 · Cited by 17
“FGF21 (Fibroblast growth factor-21) is secreted by the liver in response to a variety of nutritional challenges, particularly settings of low protein, high carbohydrate, or high alcohol consumption (Dushay et al., 2015; Laeger et al., 2014; Soberg et al., 2018; Solon-Biet et al., 2016).”
Self-citationChalvon‐Demersay, T., Moro, J., Even, P. C., Chaumontet, C., Tomé, D., Avérous, J., Piedcoq, J., Gaudichon, C., Maurin, A., Fafournoux, P., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00022.2019 · Cited by 18
“(13) also reported that the higher food intake observed with LP diets was suppressed in GCN2-KO and FGF21-deficient mice, suggesting that FGF21 is responsible for the higher intake observed with LP diets.”
BackgroundFibroblast growth factor 21 and protein energy wasting in hemodialysis patients
Post, A., Groothof, D., Schutten, J. C., Kelly, D., Swarte, J. C., Flores-Guerrero, J. L., van der Veen, Y., Kema, I. P., Özyilmaz, A., Enya, A., et al. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.01.036 · Cited by 16
Janzi, S., González-Padilla, E., Najafi, K., Ramne, S., Ahlqvist, E., Borné, Y., & Sonestedt, E. (2021) · Nutrients · doi:10.3390/nu13113954 · Cited by 15
Wei, S., Li, C., Luo, X., Yang, L., Yu, L., Wang, Q., Meng, Z., Wang, T., & Chen, Y. (2021) · 中国科学通报：英文版 · doi:10.1016/j.scib.2021.12.024 · Cited by 16
McCarty, M. F. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2015-0056 · Cited by 16
Garcia‐Caraballo, S., Comhair, T. M., Dejong, C. H. C., Lamers, W. H., & Köhler, E. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.04.022 · Cited by 16
Spring, S., Singh, A., Zapata, R. C., Chelikani, P. K., & Pezeshki, A. (2019) · Nutrients · doi:10.3390/nu11030707 · Cited by 16
“The enhanced energy intake and energy expenditure are often accompanied by a reduction in body weight and body lean mass [6,8,14,18,19] with either an increase [4,6,18,19] or no change in body fat mass [8,14,20,21].”
BackgroundHope, D. C. D., & Tan, T. M.-M. (2023) · Peptides · doi:10.1016/j.peptides.2023.170962 · Cited by 16
Role of peptide hormones in the adaptation to altered dietary protein intake
Rose, A. J. (2019) · Nutrients · doi:10.3390/nu11091990 · Cited by 15
“In response to dietary protein restriction, food intake is heightened along with energy expenditure, effects that require liver-derived FGF21 [60,61,101,103].”
BackgroundFang, H., Stone, K. P., Ghosh, S., Forney, L. A., & Gettys, T. W. (2021) · Nutrients · doi:10.3390/nu13082609 · Cited by 15
Self-citationNishi, H., Uchida, K., Saito, M., Yamanaka, D., Nagata, H., Tomoshige, H., Miyata, I., Ito, K., Toyoshima, Y., Takahashi, S., et al. (2022) · Cells · doi:10.3390/cells11091523 · Cited by 15
“Similar to those in previous studies reported [16], LP feeding moderately increased food intake.”
ResultVolcko, K. L., & McCutcheon, J. E. (2022) · Physiology & Behavior · doi:10.1016/j.physbeh.2022.113994 · Cited by 15
Eleftheriadis, T., Pissas, G., Sounidaki, M., Antoniadis, N., Antoniadi, G., Liakopoulos, V., & Stefanidis, I. (2017) · International Urology and Nephrology · doi:10.1007/s11255-017-1596-9 · Cited by 15
“GCN2 kinase sensitizes amino acid deprivation in a quite sensitive way, as only a two-day low protein diet in rats is adequate enough of inducing phosphorylation of eIF2α in the liver [23].”
Background24-h severe energy restriction impairs postprandial glycaemic control in young, lean males
Clayton, D. J., Biddle, J., Maher, T., Funnell, M. P., Sargeant, J. A., King, J. A., Hulston, C. J., Stensel, D. J., & James, L. J. (2018) · British Journal Of Nutrition · doi:10.1017/s0007114518002568 · Cited by 14
“FGF21 is a novel hepatokine secreted in response to fasting and feeding cycles((40)), which positively correlates with obesity, type 2 diabetes, insulin resistance and impaired glucose tolerance in humans((41,42)).”
BackgroundExploring endocrine FGFs - structures, functions and biomedical applications
Phan, P. (2024) · International Journal of Biochemistry and Molecular Biology · doi:10.62347/palk2137 · Cited by 16
Geroprotective interventions in the 3xTg mouse model of Alzheimer’s disease
Sonsalla, M. M., & Lamming, D. W. (2023) · GeroScience · doi:10.1007/s11357-023-00782-w · Cited by 17
“FGF21 is strongly induced by protein restriction in both humans and rodents [152, 153], and is required for some of the effects”
BackgroundFGF21 mediating the Sex-dependent Response to Dietary Macronutrients
Sauza, K. A. S., & Ryan, K. K. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae363 · Cited by 14
Yuan, X., Huang, H., Huang, Y., Wang, J., Yan, J., Ding, L., Zhang, C., & Zhang, L. (2017) · Experimental Biology and Medicine · doi:10.1177/1535370217694435 · Cited by 14
Zapata, R. C., Singh, A., Pezeshki, A., & Chelikani, P. K. (2018) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2018.12.006 · Cited by 14
Kiluk, P., Baran, A. M., Kaminski, T. W., Maciaszek, M., & Flisiak, I. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122206 · Cited by 15
Effects of dietary macronutrients on the hepatic transcriptome and serum metabolome in mice
Wu, Y., Green, C. L., Wang, G., Yang, D., Li, L., Li, B., Wang, L., Li, M., Li, J., Xu, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13585 · Cited by 13
“…several studies which explored amino acid restriction or protein restriction effects on metabolism of mice, including, for example, leucine deprivation and methionine restriction, showed downregulation of liver lipogenic genes (Anthony et al., 2013; Guo & Cavener, 2007; Laeger et al., 2014).”
BackgroundInfluentialHua, L., Li, J., Yang, Y., Jiang, D., Jiang, X., Han, X., Jin, C., Feng, B., Che, L., Xu, S., et al. (2023) · The FASEB Journal · doi:10.1096/fj.202202031r · Cited by 14
Periodized low protein-high carbohydrate diet confers potent, but transient, metabolic improvements
Li, Z., Rasmussen, M. L., Li, J., Henríquez‐Olguín, C., Knudsen, J. R., Madsen, A. B., Sanchez-Quant, E., Kleinert, M., & Jensen, T. E. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.08.008 · Cited by 15
Even, P. C., Gehring, J., & Tomé, D. (2021) · Obesity Reviews · doi:10.1111/obr.13194 · Cited by 17
“were increased after intracerebroventricular infusion of FGF21 without affecting body composition,(71) and the increase in food intake induced by low-protein diets was not observed in FGF21-knockout mice.(65)”
BackgroundOxidative phosphorylation and fatty acid oxidation in slow-aging mice
Elmansi, A. M., & Miller, R. A. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.08.018 · Cited by 14
The impacts of different dietary restriction regimens on aging and longevity: from yeast to humans
Ching, T., & Hsu, A. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-025-01188-w · Cited by 17
“It has also been reported that both the hepatic expression and circulating level of FGF21 are elevated in response to chronic PR in both rodents and humans [70, 164].”
Fibroblast growth factor 21 and dietary macronutrient intake in female mice
Wu, C.-T., Larson, K. R., Goodson, M. L., & Ryan, K. K. (2022) · Physiology & Behavior · doi:10.1016/j.physbeh.2022.113995 · Cited by 13
“First, we used casein as the sole source of dietary protein, to allow 293 for continuity with the original literature describing FGF21 as a signal of dietary protein restriction [12,13,17] 294 and with previous studies in male mice [11,14].”
MethodHypocaloric Diet Prevents the Decrease in FGF21 Elicited by High Phosphorus Intake
Pineda, C., Ríos, R., Raya, A. I., Rodríguez, M., Aguilera‐Tejero, E., & Lopez, I. (2018) · Nutrients · doi:10.3390/nu10101496 · Cited by 13
“More recent data indicate that protein restriction rather than calorie restriction is responsible for the increase in FGF21 in response to starvation [32].”
BackgroundWada, Y., Izumi, H., Shimizu, T., & Takeda, Y. (2019) · Journal of Nutrition · doi:10.1093/jn/nxz223 · Cited by 13
Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice
Albarazanji, K. A., Jennis, M., Cavanaugh, C., Lang, W., Singh, B., Lanter, J. C., Lenhard, J. M., & Hornby, P. J. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00404.2018 · Cited by 13
“In mice, liver FGF21 mRNA expression is increased within 24 h of reduced protein intake, resulting in higher circulating FGF21 levels (23).”
BackgroundEffect of nighttime light exposure on glucose metabolism in protein-restricted mice
Borck, P. C., Rickli, S., Vettorazzi, J. F., Batista, T. M., Boschero, A. C., Vieira, E., & Carneiro, E. M. (2021) · Journal of Endocrinology · doi:10.1530/joe-21-0133 · Cited by 13
Elmansi, A. M., & Miller, R. A. (2023) · GeroScience · doi:10.1007/s11357-023-00849-8 · Cited by 13
Protein Restriction in Metabolic Health: Lessons from Rodent Models
Na, K., & Park, Y. J. (2024) · Nutrients · doi:10.3390/nu16020229 · Cited by 12
“Lack of dietary protein intake increases general control nonderepressible 2 (GCN2), which is involved in controlling amino acid metabolism by detecting nutrient deficiency in the liver and then inducing eukaryotic initiation factor 2 (eIF2 α ) phosphorylation [4,40,43].”
BackgroundInfluentialKim, S. Q., Spann, R. A., Khan, M. S. H., Berthoud, H., Münzberg, H., Albaugh, V. L., He, Y., McDougal, D. H., Soto, P. L., Yu, S., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110010 · Cited by 10
Self-citationCharacterization of FGF21 Sites of Production and Signaling in Mice
Sullivan, A. I., Jensen-Cody, S. O., Claflin, K. E., Vorhies, K., Flippo, K. H., & Potthoff, M. J. (2024) · Endocrinology · doi:10.1210/endocr/bqae120 · Cited by 11
Torres, F., Khan, M. S. H., Fernandez‐Kim, S. O., Spann, R. A., Albarado, D. C., Wagner, T. J., Morrison, C. D., & Soto, P. L. (2022) · Journal of the Experimental Analysis of Behavior · doi:10.1002/jeab.745 · Cited by 13
Self-citationDietary interventions and molecular mechanisms for healthy musculoskeletal aging
Murphy, A. W., Vyavahare, S. S., Kumar, S., Lee, T. J., Sharma, A. K., Adusumilli, S., Hamrick, M. W., Isales, C. M., & Fulzele, S. (2022) · Biogerontology · doi:10.1007/s10522-022-09970-1 · Cited by 13
Vilela, D. L. D. S., da Silva, A., Pinto, S. L., & Bressan, J. (2023) · Obesity Reviews · doi:10.1111/obr.13559 · Cited by 12
Characterization of methionine dependence in melanoma cells
Garg, S., Morehead, L. C., Bird, J. T., Graw, S., Gies, A. J., Storey, A. J., Tackett, A. J., Edmondson, R. D., Mackintosh, S. G., Byrum, S. D., et al. (2023) · Molecular Omics · doi:10.1039/d3mo00087g · Cited by 12
Dietary branched chain amino acids and metabolic health: when less is more
Hill, C. M., & Morrison, C. D. (2018) · The Journal of Physiology · doi:10.1113/jp275613 · Cited by 12
“Finally, a growing body of work implicates the metabolic hormone fibroblast growth factor 21 (FGF21) as a key mediator of dietary protein restriction (Laeger et al. 2014), but its contribution to the effect of BCAA restriction remains unclear.”
BackgroundSelf-citationAlemán, G., Castro, A. L., Vigil‐Martínez, A., Torre-Villalvazo, I., Díaz‐Villaseñor, A., Noriega, L. G., Vera, I., Ordáz, G., Torres, N., & Tovar, A. R. (2019) · Genes & Nutrition · doi:10.1186/s12263-019-0642-x · Cited by 12
Ueno, S., Seino, Y., Hidaka, S., Maekawa, R., Takano, Y., Yamamoto, M., Hori, M., Yokota, K., Masuda, A., Himeno, T., et al. (2022) · Nutrients · doi:10.3390/nu14050975 · Cited by 12
“However, production of FGF21 is also regulated by protein intake and is increased by low-protein diets [31,37].”
BackgroundEvidence for the protein leverage hypothesis in preschool children prone to obesity
Zhang, H., Senior, A. M., Saner, C. C. S., Olsen, N. J., Larsen, S. C., Simpson, S. J., Raubenheimer, D., & Heitmann, B. L. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.09.025 · Cited by 11
Maternal macronutrient intake effects on offspring macronutrient targets and metabolism
Freire, T., Clark, X., Pulpitel, T., Bell-Anderson, K. S., Ribeiro, R. V., Raubenheimer, D., Crean, A. J., Simpson, S. J., & Solon‐Biet, S. M. (2024) · Obesity · doi:10.1002/oby.23995 · Cited by 11
“In mice, FGF21 is elevated in circulation under LP feeding and acts via the brain to stimulate selection of higher protein intake under choice feeding conditions and increased food intake when animals are confined to LP diets [33 – 35].”
BackgroundRobledo, A. I. U., Giralt, M., González-Galarza, F. F., Villarroya, F., Pérez, A. A. M., Ruíz-Flores, P., Pérez, M. E. G., Domingo, P., & López-Márquez, F. C. (2021) · PLoS ONE · doi:10.1371/journal.pone.0252144 · Cited by 11
A novel amino acid signaling process governs glucose-6-phosphatase transcription
Fukushima, S., Nishi, H., Kumano, M., Yamanaka, D., Kataoka, N., Hakuno, F., & Takahashi, S. (2021) · iScience · doi:10.1016/j.isci.2021.102778 · Cited by 12
Qian, Z., Zhang, Y., Yang, N., Nie, H., Yang, Z. L., Luo, P., Wei, X., Guan, Y., Huang, Y., Yan, J., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.984828 · Cited by 11
“FGF21 as an endocrine signal of protein restriction, could be highly upregulated by a low-protein diet and in turn shifts macronutrient preference to increase protein appetite and intake through neural circuits in a b-klotho-dependent manner (6, 22).”
BackgroundExpression of fibroblast growth factor 21 in patients with biliary atresia
Li, D., Lu, T., Shen, C., Liu, Y., Zhang, J., Shan, Y., Luo, Y., Xi, Z., Qiu, B., Chen, Q., et al. (2016) · Cytokine · doi:10.1016/j.cyto.2016.03.003 · Cited by 11
Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice
Ziros, P. G., Zagoriti, Z., Lagoumintzis, G., Kyriazopoulou, V. E., Iskrenova, R. P., Habeos, E. E., Sykiotis, G. P., Chartoumpekis, D. V., & Habeos, I. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0162024 · Cited by 11
“In addition to nutritional stress[10–12], expression of Fgf21 is affected by amino acid deprivation [13], chemicals such as acetaminophen or dioxin [14, 15], cold conditions[16–18], oxidative stress, mitochondrial stress[19–21] and ER stress[22–24].”
BackgroundResponse of Liver Metabolic Pathways to Ketogenic Diet and Exercise Are Not Additive
Huang, T.-Y., Goldsmith, F., Fuller, S. E., Simon, J., Batdorf, H. M., Scott, M. C., Essajee, N. M., BROWN, J. M., Burk, D. H., Morrison, C. D., et al. (2019) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002105 · Cited by 11
Self-citationHollstein, T., Basolo, A., Ando, T., Krakoff, J. A., & Piaggi, P. (2021) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab209 · Cited by 11
“FGF21 has been previously reported as a signal of protein restriction (37).”
BackgroundWisse, L. E., Visser, D., ter Braak, T. J., Bakkali, A., Struys, E. A., Morrison, C. D., van der Knaap, M. S., & Abbink, T. E. M. (2020) · Nutritional Neuroscience · doi:10.1080/1028415x.2020.1846356 · Cited by 10
“The low protein diet previously resulted in ISR activation in liver in mice.(15,21) Interestingly, in these experiments the mRNA encoding fibroblast growth factor 21 (Fgf21) was significantly increased in expression in liver upon the low protein diet, while the mRNA levels of acyl-CoA desaturase 1 (Scd1) and sterol re…”
BackgroundMethodInfluentialSelf-citationShort-term hypercaloric carbohydrate loading increases surgical stress resilience by inducing FGF21
Agius, T., Emsley, R., Lyon, A., MacArthur, M. R., Kiesworo, K., Faivre, A., Stavart, L., Lambelet, M., Legouis, D., de Seigneux, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44866-3 · Cited by 10
“This is a conserved response, with circulating FGF21 increased 10-fold in rodents and approximately 2-fold in humans fed a low-protein (LP) diet for one month 32 .”
BackgroundResultInfluentialWu, C.-T., Magaña, D. G., Roshgadol, J., Tian, L., & Ryan, K. K. (2024) · Appetite · doi:10.1016/j.appet.2024.107673 · Cited by 11
Ramne, S., García‐Ureña, M., Gillum, M. P., Ängquist, L. H., Hansen, T., Merino, J., & Grarup, N. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102049 · Cited by 11
“Long-term effects of dietary habits on fasting FGF21 has previously been suggested from a few randomized dietary interventions in humans [14,45,46], but distinguishing between randomly allocated diet interventions and self-selected diet is of importance in this context, as FGF21 also regulates…”
Xu, J., Zhang, R., Millischer, V., Stiernborg, M., Tume, C. E., Mehdinia, S., Barker, P., Yılmaz, Z., Gonçalves, V. F., Lavebratt, C., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03425-0 · Cited by 10
“This despite that FGF21 expression is reported to be strongly induced by fasting [55] and protein restriction [56], and regulates energy homeostasis during starvation [55].”
FGF21 Analogues and MASLD: A Summary of Preclinical and Clinical Data
Boutari, C., Triantafyllou, A., Papalavrentios, L., Goulis, I., & Sinakos, E. (2025) · Current Pharmaceutical Design · doi:10.2174/0113816128374854250709050425 · Cited by 11
Parsing the Potential Neuroendocrine Actions of FGF21 in Primates
Gillum, M. P. (2018) · Endocrinology · doi:10.1210/en.2018-00208 · Cited by 9
Practical prospects for boosting hepatic production of the “pro-longevity” hormone FGF21
McCarty, M. F. (2015) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2015-0057 · Cited by 10
“Whether vegans do indeed have higher levels of FGF21 has not been assessed; however, in a controlled clinical overfeeding study, serum FGF21 rose markedly – roughly 3-fold-in the subjects fed a low-protein diet (5% of calories), but not a diet of comparable calorie content providing 15% protein [64].”
BackgroundIto, S., Hosaka, T., Yano, W., Ito, T., Yasumura, M., Shimizu, Y., Kobayashi, H., Nakagawa, T., Inoue, K., Tanabe, S., et al. (2018) · Physiological Reports · doi:10.14814/phy2.13642 · Cited by 9
“…reports described suppression of body weight gain with a high-protein diet (Garcia-Caraballo et al. 1832; Petzke et al. 2014), while other prior studies demonstrated a low-protein diet to reduce body weight gain mediated by energy expenditure via the upregulation of FGF21 (Laeger et al. 2014).”
ResultInfluentialArndt, M. B., Richardson, B. A., Mahfuz, M., Ahmed, T., Haque, R., Gazi, M. A., John-Stewart, G. C., Denno, D. M., Scarlett, J. M., & Walson, J. L. (2019) · Current Developments in Nutrition · doi:10.1093/cdn/nzz024 · Cited by 10
“Protein deprivation in particular appears to drive increases in circulating FGF21, as plasma concentrations in healthy adults increased markedly after 28 d of a low-protein diet but did not change in controls who were not protein restricted (14).”
BackgroundEleftheriadis, T., Pissas, G., Sounidaki, M., Antoniadi, G., Rountas, C. D., Liakopoulos, V., & Stefanidis, L. (2017) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-016-2915-7 · Cited by 11
“This pathway is very sensitive, since a two-day low-protein diet in rats induces eIF2α phosphorylation in the liver [9].”
BackgroundThe Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review
Sadowska, A., Poniedziałek‐Czajkowska, E., & Mierzyński, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417298 · Cited by 9
Rouskas, K., Bocher, O., Simistiras, A., Emmanouil, C., Mantas, P., Skoulakis, A., Park, Y., Dimopoulos, A. C., Glentis, S., Kastenmüller, G., et al. (2025) · npj Metabolic Health and Disease · doi:10.1038/s44324-025-00057-2 · Cited by 7
“Methionine restriction also downregulates mTORC1 activity, driving increased levels of FGF21 and improved metabolic pro fi les 2,24,36 .”
Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice
Trautman, M. E., Green, C. L., MacArthur, M. R., Chaiyakul, K., Alam, Y. H., Yeh, C., Babygirija, R., James, I., Gilpin, M., Zelenovskiy, E., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102248 · Cited by 10
“The increased energy expenditure of B6 males on a PR diet is mediated by fibroblast growth factor 21 (FGF21), a key energy balance hormone that is induced by PR in both humans and rodents, and which promotes the beiging of white adipose tissue [50 — 52].”
Low- and high-protein diets do not alter ex vivo insulin action in skeletal muscle
Li, Z., Rasmussen, M. L., Li, J., Henríquez‐Olguín, C., Knudsen, J. R., Søgaard, O. S., Madsen, A. B., & Jensen, T. E. (2018) · Physiological Reports · doi:10.14814/phy2.13798 · Cited by 8
“Mechanistically, release of the stress hormone FGF21 from the liver is a hallmark response to LPHC diets and FGF21 is required for many of the beneficial effects of low-protein diets, including the effects on whole-body insulin-sensitivity (Laeger et al. 2014; Fontana et al. 2016; Maida et al. 2016).”
BackgroundSolomon, T. P. J., Carter, S., Haus, J. M., Karstoft, K., von Holstein‐Rathlou, S., Nielsen, M. S., & Gillum, M. P. (2022) · PeerJ · doi:10.7717/peerj.12755 · Cited by 10
“…effect of protein depletion on FGF21 production have reported up to 6-fold increases but are complicated by the fact that these subjects, in addition to eating less protein, also consumed more energy and carbohydrate overall to maintain caloric balance ( Laeger et al., 2014 ; Maida et al., 2016 ).”
Biology of Stress Responses in Aging
Calubag, M. F., Ademi, I., Yeh, C., Babygirija, R., Bhoopat, A. M., Kasza, I., Sonsalla, M. M., Green, C. L., Pak, H. H., & Lamming, D. W. (2023) · doi:10.59368/agingbio.20230002 · Cited by 10
Fournier, C., Rizzoli, R., Bouzakri, K., & Ammann, P. (2016) · Osteoporosis International · doi:10.1007/s00198-016-3666-8 · Cited by 9
“Moreover, amino acid deprivation increases circulating levels of Fibroblast Growth Factor 21 (FGF21) [7, 10, 11], a hepatokine shown”
BackgroundIbrahim, M. A., Bonfiglio, S. M., Schlögl, M., Vinales, K. L., Piaggi, P., Venti, C. A., Walter, M. F., Krakoff, J. A., & Thearle, M. S. (2017) · Obesity · doi:10.1002/oby.22068 · Cited by 9
“FGF21 increases with fasting and is associated with increased food intake in rodents after fasting or protein restriction (39).”
BackgroundHunger and Satiety: Linking Mechanisms, Behavior and Evolution
Raubenheimer, D., & Simpson, S. J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809633-8.20881-9 · Cited by 9
Fibroblast growth factor 21 and dietary interventions: what we know and what we need to know next
Jin, T. (2022) · Medical Review · doi:10.1515/mr-2022-0019 · Cited by 8
“Furthermore, effects of PR on food intake, energy expenditure, and body weight gain alterations, were observed in wild type mice but not in FGF21 deficient mice [52].”
BackgroundRibeiro, R. V., Senior, A. M., Simpson, S. J., Tan, J., Raubenheimer, D., Couteur, D. G. L., Macia, L., Holmes, A. J., Eberhard, J., O’Sullivan, J., et al. (2024) · Aging Cell · doi:10.1111/acel.14276 · Cited by 8
“Protein restriction increases circulating FGF-21 levels and increases protein appetite (Laeger et al., 2014 ).”
Adipokines as Cardioprotective Factors: BAT Steps Up to the Plate
McLeod, K., Datta, V., & Fuller, S. E. (2025) · Biomedicines · doi:10.3390/biomedicines13030710 · Cited by 11
“In vivo and in vitro studies have revealed NRG4’s activity in restoring cardiac function and attenuating pathological remodeling [56].”
Calubag, M. F., Ademi, I., Grunow, I., Breuer, L., Babygirija, R., Lialios, P., Le, S. M., Minton, D. M., Sonsalla, M. M., Illiano, J., et al. (2025) · Aging Cell · doi:10.1111/acel.70176 · Cited by 9
Sex Differences in Ketogenic Diet Response Reveal Gonadal Hormone Interaction With FGF21 in Mice
Zhang, Y., Cochran, J. D., Souvenir, R., Tai, W. C., Xia, R., Gladwin, B. S., Barton, N. B., Pereira, R. O., & Abel, E. D. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf131 · Cited by 8
“Interestingly, KD has not been shown to significantly raise FGF21 levels in humans, unlike other dietary conditions such as starvation, high sugar intake, or dietary protein restriction [11, 24, 25, 34, 35].”
Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice
Calubag, M. F., Ademi, I., Green, C. L., Manchanayake, D. N. H., Jayarathne, H. S. M., Marshall, R. N., Le, S. M., Lialios, P., Breuer, L. E., Yakar, S., et al. (2026) · Nature Aging · doi:10.1038/s43587-026-01169-0 · Cited by 9
“The effects of PR on energy balance are mediated by fibroblast growth factor 21 (FGF21), which promotes the beiging of iWAT 14,30–33 .”
Bensalem, J., Hein, L. K., Hassiotis, S., Trim, P. J., Proud, C. G., Heilbronn, L. K., & Sargeant, T. J. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.02.035 · Cited by 8
Fibroblast Growth Factor Signaling in Development and Disease
Bollenbecker, S., Barnes, J. W., & Krick, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119734 · Cited by 8
“FGF21 has been shown to increase energy expenditure in mice and humans, leading to a reduction in body mass and adiposity [18].”
BackgroundResistance exercise protects mice from protein-induced fat accretion
Trautman, M. E., Braucher, L. N., Elliehausen, C., Zhu, W. G., Zelenovskiy, E., Green, M., Sonsalla, M. M., Yeh, C.-Y., Hornberger, T. A., Konopka, A. R., et al. (2023) · eLife · doi:10.7554/elife.91007 · Cited by 8
Fangmann, D., Geisler, C., Schlicht, K., Hartmann, K., Köpke, J., Tiede, A., Settgast, U., Türk, K., Schulte, D. M., Altmann, K., et al. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.06.006 · Cited by 8
Dietary Essential Amino Acid Restriction Promotes Hyperdipsia via Hepatic FGF21
Rusu, P. M., Chan, A. Y., Heikenwälder, M. F., Müller, O. J., & Rose, A. J. (2021) · Nutrients · doi:10.3390/nu13051469 · Cited by 6
Sostre‐Colón, J., Gavin, M. J., Santoleri, D., & Titchenell, P. M. (2022) · Endocrinology · doi:10.1210/endocr/bqac035 · Cited by 7
Geidl, B., Hochuli, M., Spinas, G. A., & Gerber, P. A. (2022) · Nutrients · doi:10.3390/nu14194169 · Cited by 9
“In contrast, both rodent and human studies demonstrated that protein restriction increases FGF21 levels [28].”
ResultA nexus of dietary restriction and gut microbiota: Recent insights into metabolic health
Wang, L., Wang, F., Xiong, L. H., Song, H., Ren, B., & Shen, X. (2023) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2023.2202750 · Cited by 10
“PR refers to reducing the protein content in the diet although PR can increase food intake, it can promote energy expenditure and reduce bodyweight and adiposity (Laeger et al. 2016; Laeger et al. 2014).”
Perirenal Adipose Tissue: Clinical Implication and Therapeutic Interventions
Fazeli, S. A., Nourollahi, S., Alirezaei, A., Mirhashemi, S. H., Davarian, A., & Hosseini, I. (2024) · Indian Journal of Nephrology · doi:10.25259/ijn_532_23 · Cited by 7
Lauer, J. M., Pyykkö, J., Chembe, M., Bilima-Mulenga, T., Sikazwe, D., Chibwe, B., Henderson, S., Parkerson, D., Leppänen, J. M., Fink, G., et al. (2024) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2024.114408 · Cited by 7
Functions of FGF21 and its role in cardiac hypertrophy
Chen, L., Gao, M., Ong, S., & Gong, G. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.03.007 · Cited by 7
“A low-protein (LP) diet or ERS activated the PERK-eIF2a-ATF4 pathway, elevating FGF21 expression [46,78] in mice and rats.”
Relationship Between the Serum FGF21 Level and Growth in Children of Short Stature
Lee, Y. J., Jung, S. Y., Lee, Y. A., Kim, J. H., Lee, S. Y., & Shin, C. H. (2023) · Journal of Korean Medical Science · doi:10.3346/jkms.2023.38.e63 · Cited by 7
Li, X., Zheng, K., Gu, W., Hou, X., Guan, Y., Liu, L., Hou, L., Geng, J., & Song, G. (2023) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s410457 · Cited by 7
“Several studies have found that low-protein diets can stimulate FGF21 secretion.(6,7) A more recent study has revealed that FGF21 can acutely respond to an oral glucose tolerance test.”
Background
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
