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 101–200 of 590
Hydes, T., Ravi, S., Loomba, R. S., & Gray, M. E. (2020) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2020.0067 · Cited by 90
Crujeiras, A. B., Gómez-Arbeláez, D., Zulet, M. Á., Carreira, M. C., Sajoux, I., de Luis, D. A., Castro, A. I., Baltar, J., de la Torre, I. B., Sueiro, A. M., et al. (2017) · International Journal of Obesity · doi:10.1038/ijo.2017.138 · Cited by 83
“Dietaly”: practical issues for the nutritional management of CKD patients in Italy
D’Alessandro, C., Piccoli, G. B., Calella, P., Brunori, G., Pasticci, F., Egidi, M. F., Capizzi, I., Bellizzi, V., & Cupisti, A. (2016) · BMC Nephrology · doi:10.1186/s12882-016-0296-5 · Cited by 82
“When protein restriction is needed, high energy intake is mandatory to spare protein from being used as energy substrate, and allow a normal metabolic adaptation to a low protein intake [7, 8].”
BackgroundCentral Amino Acid Sensing in the Control of Feeding Behavior
Heeley, N., & Blouet, C. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00148 · Cited by 85
“FGF21 circulating levels are dramatically increased in response to LP diets in mice, rats, and humans (91), and remarkably, Fgf21 knockout mice are protected against the metabolic effects of LP diets (114).”
BackgroundCirculating FGF21 Levels in Human Health and Metabolic Disease
Keuper, M., Häring, H., & Staiger, H. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0879-2968 · Cited by 83
“7-fold increase in circulating FGF21 levels after 4 weeks [43] and to 2-fold increase after 6 weeks [44].”
BackgroundWu, Y., Li, B., Li, L., Mitchell, S. E., Green, C. L., D’Agostino, G., Wang, G., Wang, L., Li, M., Li, J., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.01.017 · Cited by 77
Normal and Pathological NRF2 Signalling in the Central Nervous System
Heurtaux, T., Bouvier, D. S., Bénani, A., Helgueta, S., Frauenknecht, K. B. M., Mittelbronn, M. G. A., & Sinkkonen, L. (2022) · Antioxidants · doi:10.3390/antiox11081426 · Cited by 79
Haro, D., Marrero, P. F., & Relat, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061386 · Cited by 79
“In line with a leucine-deprived diet, the effects on lipid metabolism, food intake and EE observed in LPD are blunted in FGF21 liver-specific knockout mice (LFgf21KO), showing that FGF21 is involved in the metabolic response to protein-restricted diets [108,110].”
BackgroundZonated leucine sensing by Sestrin-mTORC1 in the liver controls the response to dietary leucine
Cangelosi, A. L., Puszynska, A. M., Roberts, J. M., Armani, A., Nguyen, T. P., Spinelli, J. B., Kunchok, T., Wang, B., Chan, S. H., Lewis, C. A., et al. (2022) · Science · doi:10.1126/science.abi9547 · Cited by 75
Schlögl, M., Piaggi, P., Pannacciuli, N., Bonfiglio, S. M., Krakoff, J., & Thearle, M. S. (2015) · Diabetes · doi:10.2337/db15-0382 · Cited by 65
“A candidate pathway that might explain these findings is the hepatic response to amino acid deprivation that leads to secretion of fibroblast growth factor 21 (FGF21) (26,27).”
BackgroundInfluentialRegulation of metabolic health and aging by nutrient-sensitive signaling pathways
Richardson, N. E., & Lamming, D. W. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.11.014 · Cited by 73
“Mice fed a low protein diet have increased levels of the fasting-induced insulinsensitizing hormone FGF21, which is believed to mediate the increased energy expenditure of mice on a low protein diet (Fontana et al., 2016a; Laeger et al., 2014).”
BackgroundTrautman, M. E., Richardson, N. E., & Lamming, D. W. (2022) · Aging Cell · doi:10.1111/acel.13626 · Cited by 68
“As FGF21 is essential for the metabolic benefits and lifespan extension of PR (Hill et al., 2022; Laeger et al., 2014) (Figure 3), and as BCAA and isoleucine addback to a PR diet blunts or eliminates these metabolic benefits (Yu et al., 2021), it is logical to hypothesize that FGF21 is essential…”
BackgroundSamms, R. J., Cheng, C. C., Kharitonenkov, A., Gimeno, R. E., & Adams, A. C. (2016) · Endocrinology · doi:10.1210/en.2015-1722 · Cited by 76
FGF21 Is a Hormonal Mediator of the Human “Thrifty” Metabolic Phenotype
Vinales, K. L., Begaye, B., Bogardus, C., Walter, M. F., Krakoff, J. A., & Piaggi, P. (2018) · Diabetes · doi:10.2337/db18-0696 · Cited by 72
“In the current study including healthy subjects with normal glucose regulation, FGF21 concentrations increased in nearly all subjects by approximately threefold after 1 day of low-protein overfeeding, in line with what was reported in previous studies (10,13).”
BackgroundResultFasting-induced hormonal regulation of lysosomal function
Chen, L., Wang, K., Long, A., Jia, L., Zhang, Y., Deng, H., Li, Y., Han, J., & Wang, Y. (2017) · Cell Research · doi:10.1038/cr.2017.45 · Cited by 71
Spann, R. A., Morrison, C. D., & den Hartigh, L. J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.802541 · Cited by 76
“Further studies suggest that FGF21 increases in ketogenic diet-fed mice due to the low protein content of these diets, and not in response to ketones per se, and is thus a response to protein restriction (46, 53).”
BackgroundInfluentialSelf-citationRader, D. J., Maratos-Flier, E., Nguyen, A., Hom, D., Ferriere, M., Li, Y., Kompa, J., Martic, M., Hinder, M., Basson, C. T., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab624 · Cited by 72
Homeostatic sensing of dietary protein restriction: a case for FGF21
Hill, C. M., Berthoud, H.-R., Münzberg, H., & Morrison, C. D. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.06.002 · Cited by 68
Self-citationFibroblast growth factor-21 controls dietary protein intake in male mice
Larson, K. R., Chaffin, A. T.-B., Goodson, M. L., Fang, Y., & Ryan, K. K. (2019) · Endocrinology · doi:10.1210/en.2018-01056 · Cited by 68
“and colleagues (15) and Morrison and colleagues (17) agree with this interpretation.”
BackgroundFGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue
Markan, K. R., Naber, M. C., Small, S. M., Peltekian, L., Kessler, R. L., & Potthoff, M. J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.03.009 · Cited by 70
“For example, plasma FGF21 levels are elevated in both rodents and humans in response to high carbohydrate levels [4e6], protein restriction [7,8], fasting [9e14], and obesity and insulin resistance [14e22].”
BackgroundMaida, A., Chan, J. S. K., Sjøberg, K. A., Zota, A., Schmoll, D., Kiens, B., Herzig, S., & Rose, A. J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.06.009 · Cited by 68
“More recently, the physiological context of FGF21 has been increasingly explored [17e19], with several studies from diverse laboratories now having shown that it is an endocrine signal of dietary PD in rodents [5,20e25] and in humans [5,21,26,27].”
BackgroundInfluentialSex differences in the hormonal and metabolic response to dietary protein dilution
Larson, K. R., Russo, K. A., Fang, Y., Mohajerani, N., Goodson, M. L., & Ryan, K. K. (2017) · Endocrinology · doi:10.1210/en.2017-00331 · Cited by 66
“Protein dilution and energy balance Several recent studies report a profound effect of dietary protein dilution to decrease feeding efficiency while improving metabolic health in male mice (1, 5, 6).”
BackgroundMethodInfluentialGlycine homeostasis requires reverse SHMT flux
McBride, M. J., Hunter, C. J., Zhang, Z., TeSlaa, T. A., Xu, X., Ducker, G. S., & Rabinowitz, J. D. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.001 · Cited by 71
The Effects of Nutrition on Linear Growth
Inzaghi, E., Pampanini, V., Deodati, A., & Cianfarani, S. (2022) · Nutrients · doi:10.3390/nu14091752 · Cited by 93
Protein appetite as an integrator in the obesity system: the protein leverage hypothesis
Raubenheimer, D., & Simpson, S. J. (2023) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0212 · Cited by 70
“Fibroblast growth factor 21 (FGF21) was the first discovered endocrine signal of low-protein state (protein hunger) [52].”
BackgroundMacronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health
Wali, J. A., Solon‐Biet, S. M., Freire, T., & Brandon, A. E. (2021) · Biology · doi:10.3390/biology10040336 · Cited by 74
GDF15 is a major determinant of ketogenic diet-induced weight loss
Lu, J. F., Zhu, M., Xia, B., Zhang, N., Liu, X. P., Liu, H., Zhang, R. X., Xiao, J. Y., Yang, H., Zhang, Y. Q., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.11.003 · Cited by 69
FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs
Kim, K. H., & Lee, M. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0160 · Cited by 66
“Intriguingly, the serum FGF21 level and hepatic FGF21 expression were not increased in mice with a 50% reduction in food intake without changes of protein intake (Laeger et al. 2014).”
BackgroundInfluentialFatty liver and FGF21 physiology
Maratos–Flier, E. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.05.006 · Cited by 66
Protein restriction and cancer
Yin, J., Ren, W., Huang, X., Li, T., & Yin, Y. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.03.004 · Cited by 69
A new frontier in FGF21 biology
Potthoff, M. J. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.206 · Cited by 63
Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues
Lin, X., Liu, Y. B., & Hu, H. (2017) · Biomedical Reports · doi:10.3892/br.2017.890 · Cited by 61
“This discrepancy may be caused by the low content of protein in the ketogenic diet used in the experiment with mice (70).”
BackgroundEffect of Nutrition on Statural Growth
Gat‐Yablonski, G., & Luca, F. D. (2017) · Hormone Research in Paediatrics · doi:10.1159/000456547 · Cited by 63
Laeger, T., Baumeier, C., Wilhelmi, I., Würfel, J., Kamitz, A., & Schürmann, A. (2017) · Diabetologia · doi:10.1007/s00125-017-4389-x · Cited by 59
“RD191108200R, human FGF21 ELISA; BioVendor, Brno, Czech Republic) and as described previously [3, 4].”
BackgroundMethodSelf-citationAltered nutrient status reprograms host inflammation and metabolic health via gut microbiota
Golonka, R. M., Xiao, X., Abokor, A. A., Joe, B., & Vijay–Kumar, M. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108360 · Cited by 60
“This further corresponds with previous reports that amino acid-deficient diets and low-protein diets increases FGF21 expression through GCN2eIF2α-ATF4 and PPARα signaling [101, 102].”
ResultGlucagon's Metabolic Action in Health and Disease
Zeigerer, A., Sekar, R., Kleinert, M., Nason, S. R., Habegger, K. M., & Müller, T. D. (2021) · Comprehensive physiology · doi:10.1002/cphy.c200013 · Cited by 87
“Fgf21 is secreted via coat protein complex II vesicles (400) in response to diverse nutritional stressors including fasting (11, 109, 171), a ketogenic diet (10, 11) a low protein diet (165, 218, 219), and carbohydrate refeeding (170, 330).”
Heianza, Y., Ma, W., Huang, T., Wang, T., Zheng, Y., Smith, S. R., Bray, G. A., Sacks, F. M., & Qi, L. (2016) · Diabetes Care · doi:10.2337/dc16-1111 · Cited by 60
Self-citationRegulation of amino acid metabolism and α‐cell proliferation by glucagon
Hayashi, Y., & Seino, Y. (2018) · Journal of Diabetes Investigation · doi:10.1111/jdi.12797 · Cited by 58
Amino acid transporters in the regulation of insulin secretion and signalling
Javed, K., & Fairweather, S. J. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180250 · Cited by 64
Olson, B. G., Marks, D. L., & Grossberg, A. J. (2020) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12630 · Cited by 64
Zeng, K., Tian, L., Patel, R., Shao, W., Song, Z., Liu, L., Manuel, J., Ma, X., McGilvray, I. D., Cummins, C. L., et al. (2016) · Endocrinology · doi:10.1210/en.2016-1596 · Cited by 57
“…as a novel hepatic hormone with potential in the treatment of T2D, obesity, liver steatosis, and other metabolic disorders (4, 10, 13, 14, 39, 40), great efforts have been made to explore the mechanisms underlying its production under physiological and pathophysiological conditions (16, 41 – 44).”
BackgroundWanders, D., Stone, K. P., Dille, K., Simon, J., Pierse, A., & Gettys, T. W. (2015) · BioFactors · doi:10.1002/biof.1240 · Cited by 57
“Recent work has refocused attention on dietary protein, with special emphasis on how the concentration and composition of dietary protein affects ingestive behavior (29, 32–33), energy balance [25], fecundity [26], and lifespan [27].”
BackgroundPérez‐Martí, A., Garcia‐Guasch, M., Tresserra‐Rimbau, A., Carrilho‐Do‐Rosário, A., Estruch, R., Salas‐Salvadó, J., Martínez‐González, M. Á., Lamuela‐Raventós, R., Marrero, P. F., Haro, D., et al. (2017) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600725 · Cited by 56
Maekawa, R., Seino, Y., Ogata, H., Murase, M., Iida, A., Hosokawa, K., Joo, E., Harada, N., Tsunekawa, S., Hamada, Y., et al. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.07.010 · Cited by 56
“[37] Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, et al.”
BackgroundKetogenic diet, neuroprotection, and antiepileptogenesis
Murugan, M., & Boison, D. (2020) · Epilepsy Research · doi:10.1016/j.eplepsyres.2020.106444 · Cited by 56
“Protein restriction is known to enhance the production of the endocrine signal fibroblast growth factor 21(FGF21) which in turn reduces blood glucose levels (Laeger et al., 2014) and may supplement to the neuroprotective effects of KD.”
BackgroundMacArthur, M. R., Mitchell, S. J., Trevino-Villarreal, J. H., Grondin, Y., Reynolds, J. S., Kip, P., Jung, J., Trocha, K. M., Ozaki, C. K., & Mitchell, J. R. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.06.011 · Cited by 56
Naneix, F., Peters, K. Z., & McCutcheon, J. E. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.10.036 · Cited by 55
Neural Control of Energy Expenditure
Münzberg, H., Qualls‐Creekmore, E., Berthoud, H., Morrison, C. D., & Yu, S. (2015) · Handbook of experimental pharmacology · doi:10.1007/164_2015_33 · Cited by 53
“The circulating hormone FGF21 is well known to increase energy expenditure and promote the browning of WAT (Douris et al. 2015; Fisher et al. 2012), but only recent work showed that FGF21 is required for the low protein-induced energy expenditure (Laeger et al. 2014; Morrison and Laeger 2015).”
Self-citationSpring, S., Premathilake, H., DeSilva, U., Shili, C. N., Carter, S., & Pezeshki, A. (2020) · Scientific Reports · doi:10.1038/s41598-020-60150-y · Cited by 55
Potent anti-seizure effects of D-leucine
Hartman, A. L., Santos, P. T., O’Riordan, K. J., Stafstrom, C. E., & Hardwick, J. M. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.013 · Cited by 54
“The other relevant ketogenic diet component is protein, which is minimized to induce systemic ketosis (Hartman and Vining, 2007; Laeger et al., 2014).”
BackgroundPettit, A. P., Jonsson, W. O., Bargoud, A., Mirek, E. T., Peelor, F. F., Wang, Y., Gettys, T. W., Kimball, S. R., Miller, B. F., Hamilton, K. L., et al. (2017) · Journal of Nutrition · doi:10.3945/jn.116.246710 · Cited by 53
Self-citationFougerat, A., Bruse, J., Polizzi, A., Montagner, A., Guillou, H., & Wahli, W. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101303 · Cited by 56
“As in mice, humans show increased FGF21 in response to pharmacological activation of PPAR α [188,190], as well as in response to a low protein diet [157,158] and fructose consumption [191,192].”
Harris, L.-A. L. S., Smith, G. I., Patterson, B. W., Ramaswamy, R. S., Okunade, A. L., Kelly, S. C., Porter, L. C., Klein, S., Yoshino, J., & Mittendorfer, B. (2017) · Diabetes · doi:10.2337/db16-1475 · Cited by 52
Next Generation Strategies for Geroprotection via mTORC1 Inhibition
Dumas, S. N., & Lamming, D. W. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz056 · Cited by 53
Wilson, G. J., Lennox, B. A., She, P., Mirek, E. T., Al Baghdadi, R. J. T., Fusakio, M. E., Dixon, J. L., Henderson, G. C., Wek, R. C., & Anthony, T. G. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00361.2014 · Cited by 52
Ozaki, Y., Saito, K., Nakazawa, K., Konishi, M., Itoh, N., Hakuno, F., Takahashi, S.-I., Kato, H., & Takenaka, A. (2015) · British Journal Of Nutrition · doi:10.1017/s0007114515002846 · Cited by 51
“In agreement with the results of the microarray analysis and compared with control mice, WT mice fed an isoenergetic low-protein diet for 5 and 11 d showed significantly greater plasma FGF21 levels, which were consistent with the recently published work by Laeger et al.((34)).”
BackgroundResultInfluentialHashidume, T., Kato, A., Tanaka, T., Miyoshi, S., Itoh, N., Nakata, R., Inoue, H., Oikawa, A., Nakai, Y., Shimizu, M., et al. (2016) · Scientific Reports · doi:10.1038/srep28183 · Cited by 52
Trevino-Villarreal, J. H., Reynolds, J. S., Bartelt, A., Langston, P. K., MacArthur, M. R., Arduini, A., Tosti, V., Veronese, N., Bertozzi, B., Brace, L. E., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.99470 · Cited by 50
“Like APOA5, FGF21 is elevated upon PR (20, 52) — as well as in response to sugar (53) — and has an established role in promoting TG clearance via activation of white and brown adipose tissue (43) and increasing energy expenditure via central and peripheral mechanisms — for example, through increased”
BackgroundGosby, A. K., Lau, N. S., Tam, C. S., Iglesias, M. A., Morrison, C. D., Caterson, I. D., Brand-Miller, J., Conigrave, A. D., Raubenheimer, D., & Simpson, S. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0161003 · Cited by 51
“In this study, the fasting plasma level of FGF-21 was higher following 4 d ad libitum intake of a reduced percent protein diet (10%), consistent with published work in mice and in humans [14].”
BackgroundMethodResultInfluentialSelf-citationMartin, A., Ecklu-Mensah, G., Ha, C. W. Y., Hendrick, G., Layman, D. K., Gilbert, J. A., & Devkota, S. (2021) · Nature Communications · doi:10.1038/s41467-021-24074-z · Cited by 52
Kosakamoto, H., Okamoto, N., Aikawa, H., Sugiura, Y., Suematsu, M., Niwa, R., Miura, M., & Obata, F. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00608-7 · Cited by 46
FGF21 counteracts alcohol intoxication by activating the noradrenergic nervous system
Choi, M., Schneeberger, M., Fan, W., Bugde, A., Gautron, L., Vale, K., Hammer, R. E., Zhang, Y., Friedman, J. M., Mangelsdorf, D. J., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.02.005 · Cited by 51
Gliniak, C. M., Gordillo, R., Youm, Y., Lin, Q., Crewe, C., Zhang, Z., Field, B. C., Fujikawa, T., Virostek, M., Zhao, S., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.05.011 · Cited by 53
McCarty, M. F., & Lerner, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103624 · Cited by 51
Dietary Sulfur Amino Acid Restriction and the Integrated Stress Response: Mechanistic Insights
Jonsson, W. O., Margolies, N., & Anthony, T. G. (2019) · Nutrients · doi:10.3390/nu11061349 · Cited by 51
Peng, X., Gennemark, P., O’Mahony, G., & Bartesaghi, S. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00174 · Cited by 49
“FGF21 protein is expressed in liver, pancreas, and adipose tissue and is regulated by fasting, ketogenic diet, low protein diet, PPARγ, and PPARα activation as well as glucagon action (126).”
BackgroundThe regulation of FGF21 gene expression by metabolic factors and nutrients
Erickson, A., & Moreau, R. F. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0016 · Cited by 53
“These alternative mechanisms include PPARα, which when knocked out in mouse liver elicited low serum FGF21 concentrations and weak FGF21 induction by a low-protein diet [86].”
BackgroundInfluentialChalvon‐Demersay, T., Blachier, F., Tomé, D., & Blais, A. (2017) · Frontiers in Nutrition · doi:10.3389/fnut.2017.00005 · Cited by 50
“Indeed, the increase in food intake induced under a LP diet is suppressed in FGF21-KO mice (43).”
BackgroundDerous, D., Mitchell, S. E., Wang, L., Green, C. L., Wang, Y., Chen, L., Han, J. J., Promislow, D., Lusseau, D., Douglas, A., et al. (2017) · Aging · doi:10.18632/aging.101269 · Cited by 49
“This is in stark contrast with protein and methionine restriction (PR and MR) studies where Fgf21 expression was significantly increased compared to controls [136–138].”
Zhuo, Y., Hua, L., Feng, B., Jiang, X., Li, J., Jiang, D., Huang, X., Yingguo, Z., Li, Z., Yan, L., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.02.020 · Cited by 49
“Concentrations of metabolic signals, such as amino acids, IGF1 [15,44] and FGF21 [18,45], are closely correlated to dietary protein intake levels, and are directly or indirectly associated with reproductive function.”
BackgroundFlippo, K. H., Jensen-Cody, S. O., Claflin, K. E., & Potthoff, M. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-76593-2 · Cited by 49
Mulyani, A. T., Khairinisa, M. A., Khatib, A., & Chaerunisaa, A. Y. (2025) · Nutrients · doi:10.3390/nu17091493 · Cited by 48
Mu, W., Vanhoosier, E., Elks, C. M., & Grant, R. W. (2018) · Nutrients · doi:10.3390/nu10070918 · Cited by 48
“Because dietary protein restriction can upregulate thermogenic gene mRNA expression through Fgf21 [31,32], we examined thermogenic gene expression in inguinal white adipose tissue (IWAT).”
BackgroundResultInfluentialYan, J., Wang, J., Huang, H., Huang, Y., Mi, T., Zhang, C., & Zhang, L. (2017) · PubMed Central · Cited by 48
Effect of exercise intensity on circulating hepatokine concentrations in healthy men
Willis, S. A., Sargeant, J. A., Thackray, A. E., Yates, T. E., Stensel, D. J., Aithal, G. P., & King, J. A. (2019) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2018-0818 · Cited by 48
Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity
Zhang, Y.-B., Yan, T., Wang, T., Liu, X., Hamada, K., Sun, D., Sun, Y., Yang, Y., Wang, J., Takahashi, S., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.02.004 · Cited by 49
Dietary Methionine and Total Sulfur Amino Acid Restriction in Healthy Adults
Richie, J. P., Sinha, R., Dong, Z., Nichenametla, S. N., Ables, G. P., Ciccarella, A., Sinha, I., Calcagnotto, A., Chinchilli, V. M., Reinhart, L., et al. (2023) · The journal of nutrition health & aging · doi:10.1007/s12603-023-1883-3 · Cited by 47
“Metabolically healthy human subjects undergoing shortterm protein restriction exhibit elevated circulating FGF-21 concentrations (40-42).”
BackgroundFGF-based drug discovery: advances and challenges
Chen, G., Chen, L., Li, X., & Mohammadi, M. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01125-w · Cited by 51
Nonogaki, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031600 · Cited by 49
Metabolic roles of endocrine fibroblast growth factors
Fernandes-Freitas, I., & Owen, B. M. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.09.014 · Cited by 46
Santoso, P., Nakata, M., Shiizaki, K., Boyang, Z., Parmila, K., Otgon-Uul, Z., Hashimoto, K., Satoh, T., Mori, M., Kuro‐o, M., et al. (2017) · Scientific Reports · doi:10.1038/srep45819 · Cited by 45
Thiessen, S., Vanhorebeek, I., Derese, I., Gunst, J., & den Berghe, G. V. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2700 · Cited by 45
“Until now, a rise in circulating FGF21 concentrations in humans was only shown after prolonged metabolic disturbance ( 7 d), such as starvation or protein restriction, suggesting that FGF21 might only play a role after a long period of metabolic stress (29, 40).”
BackgroundFibroblast growth factor 21: an endocrine inhibitor of sugar and alcohol appetite
von Holstein‐Rathlou, S., & Gillum, M. P. (2019) · The Journal of Physiology · doi:10.1113/jp277117 · Cited by 44
“2007) and following intake of low-protein diets (Laeger et al. 2014; Solon-Biet et al. 2016).”
BackgroundInfluentialThe influences of low protein diet on the intestinal microbiota of mice
Masuoka, H., Suda, W., Tomitsuka, E., Shindo, C., Takayasu, L., Horwood, P. F., Greenhill, A. R., Hattori, M., Umezaki, M., & Hirayama, K. (2020) · Scientific Reports · doi:10.1038/s41598-020-74122-9 · Cited by 45
Stemmer, K., Zani, F., Habegger, K. M., Neff, C., Kotzbeck, P., Bauer, M., Yalamanchilli, S., Azad, A., Lehti, M., Martins, P. J. F., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3668-7 · Cited by 44
“This stands in contrast to previous findings by Leager et al [39] showing increased EE in mice fed a protein-restricted regular diet.”
ResultFibroblast growth factor 21 in heart failure
Tucker, W., Tucker, B., Rye, K., & Ong, K. L. (2022) · Heart Failure Reviews · doi:10.1007/s10741-022-10268-0 · Cited by 44
Toward reconciling the roles of FGF21 in protein appetite, sweet preference, and energy expenditure
Solon‐Biet, S. M., Clark, X., Bell-Anderson, K. S., Rusu, P. M., Perks, R., Freire, T., Pulpitel, T., Senior, A. M., Hoy, A. J., Aung, O., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113536 · Cited by 43
Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21
Camporez, J. P., Asrih, M., Zhang, D., Kahn, M., Samuel, V. T., Jurczak, M. J., & Jornayvaz, F. R. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0136 · Cited by 44
“However, KD has been shown to increase FGF21 levels because FGF21 is an endocrine signal of protein restriction (Laeger et al. 2014).”
BackgroundThe nutritional geometry of liver disease including non-alcoholic fatty liver disease
Simpson, S. J., Raubenheimer, D., Cogger, V. C., Macia, L., Solon‐Biet, S. M., Couteur, D. G. L., & George, J. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.10.005 · Cited by 42
Hua, L., Feng, B., Huang, L., Li, J., Luo, T. F., Jiang, X., Han, X., Che, L., Xu, S., Lin, Y., et al. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.195 · Cited by 43
Dietary protein and amino acid restriction: Roles in metabolic health and aging-related diseases
Wang, D., Ye, J., Shi, R., Zhao, B., Liu, Z., Lin, W. J., & Liu, X. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.12.009 · Cited by 46
The influence of skeletal muscle on appetite regulation
Grannell, A., VITO, G. D., Murphy, J. C., & le Roux, C. W. (2019) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2019.1618185 · Cited by 46
“[107] study investigated the behavioral and metabolic responses of wild”
BackgroundMurphy, M., Peters, K. Z., Denton, B. S., Lee, K. A., Chadchankar, H., & McCutcheon, J. E. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2017.12.011 · Cited by 42
Chaumontet, C., Azzout-Marniche, D., Blais, A., Piedcoq, J., Tomé, D., Gaudichon, C., & Even, P. C. (2019) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00316.2018 · Cited by 42
Fritsche, K., Ziková, A., Marx‐Stoelting, P., & Braeuning, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032686 · Cited by 42
“It further enhances carbohydrate disposal and increases energy expenditure in the brown adipose tissue (BAT) of newborns [79].”
BackgroundTorre-Villalvazo, I., Alemán, G., Valle‐Rios, R., & Noriega, L. G. (2019) · Nutrition Research · doi:10.1016/j.nutres.2019.06.006 · Cited by 45
Tokizane, K., Brace, C. S., & Imai, S. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.011 · Cited by 41
Ryan, K. K., Packard, A. E. B., Larson, K. R., Stout, J., Fourman, S. M., Thompson, A. M. K., Ludwick, K., Habegger, K. M., Stemmer, K., Itoh, N., et al. (2017) · Endocrinology · doi:10.1210/en.2017-00486 · Cited by 42
The regulation of healthspan and lifespan by dietary amino acids
Babygirija, R., & Lamming, D. W. (2021) · Translational Medicine of Aging · doi:10.1016/j.tma.2021.05.001 · Cited by 43
“FGF21 is believed to be a critical regulator of many of the effects of a PR diet, as experiments using mice lacking Fgf21 have found that FGF21 is required for PR-mediated changes in food intake, energy expenditure, body weight, and glucose tolerance (21, 22, 93, 94).”
BackgroundFGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury
Li, F., Liu, Z., Tang, C., Cai, J., & Dong, Z. (2018) · The FASEB Journal · doi:10.1096/fj.201701316r · Cited by 39
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
