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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Starvation, high sugar intake, and dietary protein restriction all induce circulating FGF21 levels in humans.
“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]
FGF21 is induced by protein restriction through pathways dependent on ATF4 and NRF2.
“protein restriction through pathways dependent on the transcription factors ATF4 and NRF26,27.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [26]
Ketogenic diets do not induce plasma FGF21 levels in humans.
“ketogenic diets do not induce plasma FGF21 levels in humans26,30,34”
From Metabolic messengers: FGF21 (2021) · cites this paper as [26]
FGF21 is induced in response to protein imbalance, specifically dietary-protein dilution.
“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]
FGF21 is required for the increases in energy expenditure and the prevention of weight gain associated with low-protein diets.
“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]
The increase in FGF21 in response to low protein results in increased energy expenditure and lower body weight gain.
“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]
Elevation of circulating FGF21 in response to low protein increases both browning of adipose tissues and energy expenditure.
“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]
Low-protein diets, amino acid starvation, and the amino acid-depleting drug asparaginase induce plasma FGF21 levels.
“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]
FGF21 is absolutely necessary in mice to mediate the effects of low-protein diets.
“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]
Circulating FGF21 levels fail to increase in humans in response to a ketogenic diet.
“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]
Protein restriction promotes systemic energy expenditure through elevation in plasma FGF21 levels.
“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]
FGF21 is markedly induced in response to protein restriction but not caloric restriction.
“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]
The effect of high carbohydrate and low protein to increase FGF21 appears to be regulated independently.
“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]
Liver FGF21 expression and circulating FGF21 protein levels are increased by the restriction of protein intake in mice, rats, and humans.
“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]
Reductions in dietary protein intake-or the intake of specific amino acids-increase liver FGF21 mRNA expression and circulating FGF21 protein levels.
“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]
The 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.
“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]
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.
“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]
The increase in FGF21 is absolutely required for metabolic responses to protein restriction.
“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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BackgroundSelf-citationMardinoğlu, A., Wu, H., Björnson, E., Zhang, C., Hakkarainen, A., Räsänen, S., Lee, S., Mancina, R. M., Bergentall, M., Pietiläinen, K. H., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.005 · Cited by 455 · see citing works
“Paradoxically, plasma FGF21 concentrations in rodents increase in response to low-carbohydrate ketogenic diets (Badman et al., 2007, 2009; Laeger et al., 2014).”
Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Degirolamo, C., Sabbà, C., & Moschetta, A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.9 · Cited by 424 · see citing works
The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine
Yu, D., Richardson, N. E., Green, C. L., Spicer, A. B., Trautman, M. E., Flores, V., Jang, C., Kasza, I., Nikodémová, M., Wakai, M. H., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.03.025 · Cited by 388 · see citing works
“FGF21 is induced in both humans and rodents in response to LP diets and plays a key role in the metabolic effects of such diets (Cummings et al., 2018; Fontana et al., 2016; Hill et al., 2018; Hill et al., 2019; Laeger et al., 2016; Laeger et al., 2014; Maida et al., 2016; Wanders et al., 2017).”
FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver
von Holstein-Rathlou, S., BonDurant, L. D., Peltekian, L., Naber, M. C., Yin, T. C., Claflin, K. E., Urizar, A. I., Madsen, A. N., Ratner, C., Holst, B., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.003 · Cited by 347 · see citing works
“Interestingly, consumption of low protein diets also increases hepatic and plasma FGF21 levels in humans (Laeger et al., 2014).”
Restoration of metabolic health by decreased consumption of branched‐chain amino acids
Richardson, N. E., Williams, E. M., Kasza, I., Konon, E. N., Schaid, M. D., Schmidt, B., Poudel, C., Sherman, D. S., Yu, D., Apelo, S. I. A., et al. (2017) · The Journal of Physiology · doi:10.1113/jp275075 · Cited by 338 · see citing works
“An LP diet also promotes metabolic health in rodents, reducing the accumulation of white adipose tissue (WAT) and increasing glucose tolerance and insulin sensitivity in animals fed a normal diet, as well as improving glucose homeostasis in mice fed a high-fat diet (Laeger et al. 2014; Solon-Biet et al. 2015; Fontana…”
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Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21
Owen, B. M., Mangelsdorf, D. J., & Kliewer, S. A. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.10.002 · Cited by 286 · see citing works
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
Staiger, H., Keuper, M., Berti, L., Hrabě de Angelis, M., & Häring, H.-U. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00016 · Cited by 270 · see citing works
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Inter-organ crosstalk during development and progression of type 2 diabetes mellitus
Xourafa, G., Korbmacher, M., & Roden, M. (2024) · Nature Reviews Endocrinology · doi:10.1038/s41574-023-00898-1 · Cited by 274 · see citing works
“While adiponectin, leptin, adipsin and FGF21 can possibly have beneficial effects, pro-inflammatory cytokines (such as interleukins and asprosin), selenoprotein P and fetuin A impair β-cell function 11,65,78,98,100,143,151,160,172 .”
BackgroundInfluentialRichardson, N. E., Konon, E. N., Schuster, H. S., Mitchell, A. T., Boyle, C., Rodgers, A. C., Finke, M., Haider, L. R., Yu, D., Flores, V., et al. (2021) · Nature Aging · doi:10.1038/s43587-020-00006-2 · Cited by 264 · see citing works
New insights into the mechanisms of the ketogenic diet
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Hepatokines and metabolism: Deciphering communication from the liver
Jensen-Cody, S. O., & Potthoff, M. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101138 · Cited by 252 · see citing works
“This robust increase in FGF21 results in increased energy expenditure and lower body weight gain [155,156,160,163] (Figure 2), which may function physiologically to achieve the protein leverage effect without increasing body weight [155,164].”
BackgroundImportance of circadian timing for aging and longevity
Acosta-Rodríguez, V. A., Rijo‐Ferreira, F., Green, C. B., & Takahashi, J. S. (2021) · Nature Communications · doi:10.1038/s41467-021-22922-6 · Cited by 249 · see citing works
FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism
Hill, C. M., Laeger, T., Dehner, M., Albarado, D. C., Clarke, B., Wanders, D., Burke, S. J., Collier, J. J., Qualls-Creekmore, E., Solon-Biet, S. M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.022 · Cited by 229 · see citing works
“For determination of serum FGF21, 50 ml of serum were diluted in 200 ml of dilution buffer before analysis as previously described (Laeger et al., 2014a).”
BackgroundMethodInfluentialSelf-citationFructose ingestion acutely stimulates circulating FGF21 levels in humans
Dushay, J. R., Toschi, E., Mitten, E. K., Fisher, F. M., Herman, M. A., & Maratos-Flier, E. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2014.09.008 · Cited by 233 · see citing works
Machado, S. A., Pasquarelli-do-Nascimento, G., da Silva, D. S., Farias, G. R., Santos, I. D. O., Baptista, L. B., & Magalhães, K. G. (2022) · Nutrition & Metabolism · doi:10.1186/s12986-022-00694-0 · Cited by 229 · see citing works
“Macronutrients such as proteins also regulate FGF 21 production through amino acid restriction [167].”
BackgroundFibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
BonDurant, L. D., & Potthoff, M. J. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064800 · Cited by 222 · see citing works
“FGF21 is absolutely necessary in mice to mediate the effects of low-protein diets (72, 73, 85).”
BackgroundInfluentialFGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
Søberg, S., Sandholt, C. H., Jespersen, N. Z., Toft, U., Madsen, A. L., von Holstein-Rathlou, S., Grevengoed, T. J., Christensen, K. B., Bredie, W. L. P., Potthoff, M. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.009 · Cited by 216 · see citing works
Tillman, E. J., & Rolph, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601290 · Cited by 209 · see citing works
“Thirdly, protein restriction in humans (283) and rodents (84), particularly with concomitant high-carbohydrate dietary content (284), increases circulating FGF21.”
BackgroundDefining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
Solon-Biet, S. M., Cogger, V. C., Pulpitel, T., Heblinski, M., Wahl, D., McMahon, A. C., Warren, A., Durrant-Whyte, J., Walters, K. A., Krycer, J. R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.001 · Cited by 212 · see citing works
“Although FGF21 is robustly elevated in protein/amino acid restriction, its physiological role remains uncertain (Laeger et al., 2014; Maida et al., 2016).”
InfluentialSelf-citationFGF21 and the late adaptive response to starvation in humans
Fazeli, P. K., Lun, M., Kim, S. M., Bredella, M. A., Wright, S., Zhang, Y., Lee, H., Catana, C., Klibanski, A., Patwari, P., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83349 · Cited by 214 · see citing works
“With regard to the potential therapeutic implications of this study, we cannot assume that any hypothesized functional roles of FGF21 in the starved state are relevant to supraphysiologic administration of FGF21 mimetics in patients with metabolic disease; however, this study underscores the emerging concept that the…”
BackgroundResultEffects of Ketogenic Diets on Cardiovascular Risk Factors: Evidence from Animal and Human Studies
Kosinski, C., & Jornayvaz, F. R. (2017) · Nutrients · doi:10.3390/nu9050517 · Cited by 210 · see citing works
“Finally, FGF21 has been shown to act as an endocrine signal of protein restriction [55].”
BackgroundLaeger, T., Albarado, D. C., Burke, S. J., Trosclair, L., Hedgepeth, J. W., Berthoud, H.-R., Gettys, T. W., Collier, J. J., Münzberg, H., & Morrison, C. D. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.044 · Cited by 206 · see citing works
“The mechanisms linking reduced protein intake to increased hepatic Fgf21 expression and secretion are currently unclear, but previous work implicates the amino acid sensor GCN2 (De SousaCoelho et al., 2012; Laeger et al., 2014a).”
BackgroundMethodResultInfluentialSelf-citationPutting the Balance Back in Diet
Simpson, S. J., Couteur, D. G. L., & Raubenheimer, D. (2015) · Cell · doi:10.1016/j.cell.2015.02.033 · Cited by 183 · see citing works
“The mediating nutrient signaling systems controlling protein appetite are thought to involve both circulating free amino acids and lean hormonal signals such as FGF 21 (Laeger et al., 2014).”
Karusheva, Y., Kössler, T., Straßburger, K., Markgraf, D. F., Mastrototaro, L., Jeleník, T., Simon, M., Pesta, D. H., Zaharia, O., Bódis, K. B., et al. (2019) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz191 · Cited by 180 · see citing works
“The insulin-sensitizing hormone FGF21 is considered a metabolic signal of dietary protein restriction (58) and a marker of improvement of metabolic health (48) by enhancing glucose uptake in adipose tissue.”
BackgroundThe impact of dietary protein intake on longevity and metabolic health
Kitada, M., Ogura, Y., Monno, I., & Koya, D. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.04.005 · Cited by 175 · see citing works
“demonstrated that the serum levels of FGF21 specifically increase upon exposure to a LPD regardless of the overall caloric intake in both rodents and humans [31].”
BackgroundAmino acid metabolism, transport and signalling in the liver revisited.
Paulusma, C., Lamers, W., Bröer, S., & van de Graaf, S. V. D. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115074 · Cited by 162 · see citing works
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A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Maida, A., Zota, A., Sjøberg, K. A., Schumacher, J., Sijmonsma, T. P., Pfenninger, A., Christensen, M. M., Gantert, T., Fuhrmeister, J., Rothermel, U., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85946 · Cited by 170 · see citing works
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“, 2016) and protein restriction (Laeger et al., 2014; Solon-Biet et al., 2016), but is maximally induced by low-protein, high carbohydrate feeding (Solon-Biet et al.”
BackgroundFibroblast growth factor 21 and its novel association with oxidative stress
Gómez-Sámano, M. Á., Grajales-Gómez, M., Zuarth-Vázquez, J. M., Navarro-Flores, M. F., Martínez-Saavedra, M., Juárez-León, Ó. A., Morales-García, M., Enriquez-Estrada, V. M., Gomez-Perez, F. J., & Ramos, D. C. (2016) · Redox Biology · doi:10.1016/j.redox.2016.12.024 · Cited by 164 · see citing works
Brown and Beige Adipose Tissues in Health and Disease
Rui, L. (2017) · Comprehensive physiology · doi:10.1002/cphy.c170001 · Cited by 177 · see citing works
Fibroblast Activation Protein Cleaves and Inactivates Fibroblast Growth Factor 21
Dunshee, D. R., Bainbridge, T. W., Kljavin, N. M., Zavala-Solorio, J., Schroeder, A. C., Chan, R., Corpuz, R., Wong, M., Zhou, W., Deshmukh, G., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.710582 · Cited by 158 · see citing works
“Mice lacking FGF21 are refractory to diet-induced energy expenditure (12) and prone to developing NASH (8, 13, 14).”
BackgroundFGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance
Szczepańska, E., & Gietka‐Czernel, M. (2022) · Hormone and Metabolic Research · doi:10.1055/a-1778-4159 · Cited by 155 · see citing works
“FGF21 is induced by protein restriction Protein restriction activates FGF21 secretion via transcription factors ATF4 and NRF [43, 53].”
BackgroundDesai, B. N., Singhal, G., Watanabe, M., Stevanovic, D., Lundasen, T., Fisher, F. M., Mather, M. L., Vardeh, H. G., Douris, N., Adams, A. C., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.08.004 · Cited by 150 · see citing works
Amino Acid Transport Across the Mammalian Intestine
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Fibroblast growth factor-21, energy balance and obesity
Giralt, M., Gavaldà‐Navarro, A., & Villarroya, F. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.09.018 · Cited by 146 · see citing works
Antiaging diets: Separating fact from fiction
Lee, M. B., Hill, C. M., Bitto, A., & Kaeberlein, M. R. (2021) · Science · doi:10.1126/science.abe7365 · Cited by 143 · see citing works
“FGF21 is actively secreted in response to reduced dietary protein in both mice and humans and is required for metabolic improvements in response to PR (59).”
Amino Acid Sensing in Metabolic Homeostasis and Health.
Hu, X.-M., & Guo, F. (2020) · Endocrine reviews · doi:10.1210/endrev/bnaa026 · Cited by 123 · see citing works
Li, X. (2019) · Frontiers of Medicine · doi:10.1007/s11684-019-0711-y · Cited by 139 · see citing works
“In addition to its role as a regulator of integrated hepatic metabolism in multiple aspects [48, 50, [95] [96] [97] [98] , including fatty acid oxidation, ketogenesis, gluconeogenesis, and macronutrient preference, FGF21 counteracts hepatic pathologies in response to a number of nutritional and chemical insults, inclu…”
BackgroundA muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling
Shimizu, N., Maruyama, T., Yoshikawa, N., Matsumiya, R., Ma, Y., Ito, N., Tasaka, Y., Souta-Kuribara, A., Miyata, K., Oike, Y., et al. (2015) · Nature Communications · doi:10.1038/ncomms7693 · Cited by 138 · see citing works
“Metabolic stresses including energy limitation 10,11 , HFD feeding 10,15 , dietary protein restriction 19 and amino-acid depletion 14,20 , as well as endoplasmic reticulum stress 21,22 , mitochondrial dysfunction 12 and cold exposure 23 , either positively or negatively, modulate FGF21 expression…”
Wanders, D., Stone, K. P., Forney, L. A., Cortez, C. C., Dille, K. N., Simon, J., Xu, M., Hotard, E. C., Nikonorova, I. A., Pettit, A. P., et al. (2016) · Diabetes · doi:10.2337/db15-1324 · Cited by 138 · see citing works
“Our work comparing low-protein diets with dietary MR proposed the interesting possibility that hepatic detection of reduced EAAs from both diets produced integrated effects on energy balance and insulin sensitivity by inducing hepatic FGF21 (26,27).”
BackgroundSelf-citationMacronutrients and caloric intake in health and longevity
Solon‐Biet, S. M., Mitchell, S. J., de Cabo, R., Raubenheimer, D., Couteur, D. G. L., & Simpson, S. J. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0173 · Cited by 136 · see citing works
“It is increased in response to acute starvation but also in the obese/diabetic condition, with a recent study showing that low protein intake is the major stimulant for its expression in liver and subsequent increase in the circulation (Laeger et al. 2014).”
Wanders, D., Forney, L. A., Stone, K. P., Burk, D. H., Pierse, A., & Gettys, T. W. (2017) · Diabetes · doi:10.2337/db16-1212 · Cited by 137 · see citing works
“of FGF21, increased energy intake, and increased EE in WT mice, but recent work showed that the LP diet did not produce hypophagia in Fgf21 mice (52).”
BackgroundSelf-citationOne carbon metabolism in pregnancy: Impact on maternal, fetal and neonatal health
Kalhan, S. C. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.06.006 · Cited by 135 · see citing works
Hill, C. M., Albarado, D. C., Coco, L. G., Spann, R. A., Khan, M. S., Qualls-Creekmore, E., Burk, D. H., Burke, S. J., Collier, J. J., Yu, S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29499-8 · Cited by 117 · see citing works
Self-citationImpacts of essential amino acids on energy balance
Xiao, F., & Guo, F. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101393 · Cited by 130 · see citing works
“Most metabolic effects of Met restriction are FGF21-dependent.”
BackgroundInfluentialCirculating FGF21 in humans is potently induced by short term overfeeding of carbohydrates
Lundsgaard, A.-M., Fritzen, A. M., Sjøberg, K. A., Myrmel, L. S., Madsen, L., Wojtaszewski, J. F. P., Richter, E. A., & Kiens, B. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2016.11.001 · Cited by 126 · see citing works
Green, C. L., Trautman, M. E., Chaiyakul, K., Jain, R., Alam, Y. H., Babygirija, R., Pak, H. H., Sonsalla, M. M., Calubag, M. F., Yeh, C., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.005 · Cited by 124 · see citing works
Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans
Hansen, J. S., Clemmesen, J. O., Secher, N. H., Hoene, M., Drescher, A., Weigert, C., Pedersen, B. K., & Plomgaard, P. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2015.06.001 · Cited by 123 · see citing works
“In humans, free fatty acids (FFAs) [7], low protein intake independent of energy restriction [8] and glucagon [9,10] have been linked to increased plasma FGF-21.”
BackgroundFibroblast growth factor 21: a regulator of metabolic disease and health span
Xie, T., & Leung, P. S. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00101.2017 · Cited by 121 · see citing works
Regulation of longevity by FGF21: interaction between energy metabolism and stress responses
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.05.004 · Cited by 121 · see citing works
Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR
Deng, P., & Haynes, C. M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.05.002 · Cited by 119 · see citing works
Yap, Y. W., Rusu, P. M., Chan, A. Y., Fam, B. C., Jungmann, A., Solon‐Biet, S. M., Barlow, C. K., Creek, D. J., Huang, C., Schittenhelm, R. B., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16568-z · Cited by 118 · see citing works
Assini, J. M., Mulvihill, E. E., Burke, A. C., Sutherland, B. G., Telford, D. E., Chhoker, S. S., Sawyez, C. G., Drangova, M., Adams, A. C., Kharitonenkov, A., et al. (2015) · Endocrinology · doi:10.1210/en.2014-2003 · Cited by 119 · see citing works
FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process
Salminen, A., Kauppinen, A., & Kaarniranta, K. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1477-1 · Cited by 117 · see citing works
“[92] demonstrated that it was protein deficiency rather than simply caloric restriction that stimulated the appearance of FGF21 into circulation.”
BackgroundMitochondrial stress and mitokines in aging
Burtscher, J., Soltany, A., Visavadiya, N. P., Burtscher, M., Millet, G. P., Khoramipour, K., & Khamoui, A. V. (2023) · Aging Cell · doi:10.1111/acel.13770 · Cited by 116 · see citing works
“Nutritional stress, in particular protein restriction (Laeger et al., 2014), increases FGF21 transcription in and release from liver (BonDurant & Potthoff, 2018).”
BackgroundKlement, R. J., & Fink, M. K. (2016) · Oncogenesis · doi:10.1038/oncsis.2016.2 · Cited by 115 · see citing works
Zhang, C., Huang, Z., Gu, J., Yan, X., Lu, X., Zhou, S., Wang, S., Shao, M., Zhang, F., Cheng, P., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3630-8 · Cited by 113 · see citing works
“Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator with specific effects on glucose and lipid metabolism [7–9].”
BackgroundMitochondrial unfolded protein response: An emerging pathway in human diseases
Zhu, L., Zhou, Q., He, L., & Chen, L. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.013 · Cited by 113 · see citing works
Smith, G. I., Yoshino, J., Kelly, S. C., Reeds, D. N., Okunade, A., Patterson, B. W., Klein, S., & Mittendorfer, B. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.047 · Cited by 111 · see citing works
“…in muscle; (4) plasma fibroblast growth factor 21 (FGF21) (Camporez et al., 2013; Mashili et al., 2011; Xu et al., 2009; Markan et al., 2014; Laeger et al., 2014); and (5) the plasma concentration and muscle gene expression of selected inflammatory markers (Pedersen, 2007; Kirk and Klein,…”
BackgroundHoong, C. W. S., & Chua, M. W. J. (2021) · Endocrinology · doi:10.1210/endocr/bqab079 · Cited by 112 · see citing works
Ejaz, A., Martínez-Guinó, L., Goldfine, A. B., Ribas‐Aulinas, F., Nigris, V. D., Ribó, S., González-Franquesa, A., García-Rovés, P. M., Li, E., Dreyfuss, J. M., et al. (2016) · Diabetes · doi:10.2337/db15-1094 · Cited by 109 · see citing works
“Our experiments in primary hepatocytes indicate that betaineinduced increases in Fgf21 expression are likely not to be acute or direct but, rather, indirectly mediated by improvements in hepatic insulin action, transcriptional effects on PPARA or related nuclear receptor complexes (38,39,46,47), reduced lipid accumula…”
BackgroundChen, M., Liu, Y., Yang, Y., Qiu, Y., Wang, Z., Li, X., & Zhang, W. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.04.008 · Cited by 111 · see citing works
Protein-dependent regulation of feeding and metabolism
Morrison, C. D., & Laeger, T. (2015) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2015.02.008 · Cited by 106 · see citing works
“Finally, the role of FGF21 in the behavioral and metabolic responses to general dietary protein restriction was tested recently [14].”
Green, C. L., Pak, H. H., Richardson, N. E., Flores, V., Yu, D., Tomasiewicz, J. L., Dumas, S. N., Kredell, K., Fan, J. W., Kirsh, C., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.12.018 · Cited by 99 · see citing works
The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases
Yi, H.-S., Chang, J. Y., & Shong, M. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-18-0005 · Cited by 99 · see citing works
FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases
Sonoda, J., Chen, M. Z., & Baruch, A. (2017) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2017-0002 · Cited by 106 · see citing works
Methionine restriction prevents onset of type 2 diabetes in NZO mice
Castaño-Martínez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201900150r · Cited by 104 · see citing works
“After centrifugation (16,000 g, 10min), insulinwas detected by ELISA (Supplemental Table S3).”
BackgroundMethodInfluentialSelf-citationGlucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet
ROSENBAUM, M. S., Hall, K. D., Guo, J., Ravussin, É., Mayer, L. S., Reitman, M. L., Smith, S. R., Walsh, B. T., & Leibel, R. L. (2019) · Obesity · doi:10.1002/oby.22468 · Cited by 105 · see citing works
“Cytokines, inflammatory markers, and other molecules The inflammatory cytokines (CRP and IL-6), adiponectin, PYY, the insulinogenic and lipoprotein lipase-activating GIP, and the insulinogenic GLP-1 and FGF21 were stable and significantly correlated between weeks 3 and 4 and within each diet (Table 5).”
BackgroundInfluentialMetabolic fibroblast growth factors (FGFs): Mediators of energy homeostasis
Markan, K. R., & Potthoff, M. J. (2016) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2015.09.021 · Cited by 103 · see citing works
“In addition, it was also recently determined that FGF21 is induced in rodents and humans in response to dietary protein restriction [57].”
BackgroundLow protein diets produce divergent effects on energy balance
Pezeshki, A., Zapata, R. C., Singh, A., Yee, N. J., & Chelikani, P. K. (2016) · Scientific Reports · doi:10.1038/srep25145 · Cited by 103 · see citing works
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FGF21 and the physiological regulation of macronutrient preference
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Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity
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“Recent studies have revealed that a low-protein nutrition and distinct amino acids restricted diets rather than CR are responsible for the increase in healthspan and might extend lifespan in mammals [33,34,162,163].”
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“Continued research into metabolic phenotypes is warranted in order to further the development of clinical tests (e.g., measuring plasma FGF21 concentration following a lowprotein meal) that will proactively gauge individual susceptibilities to weight gain.”
BackgroundInfluentialThe pathobiology of polycystic kidney disease from a metabolic viewpoint
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“In response to protein restriction FGF21 is required to increase food intake (in order to meet the protein demand) and energy expenditure (EE) (68).”
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“Indeed, FGF21 is strongly upregulated by protein restriction [34,35], suggesting that limiting the drive to consume foods that are calorie-rich but protein poor may be adaptive after a certain threshold of intake.”
BackgroundIntestinal Amino Acid Transport and Metabolic Health
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“, 2016) and in humans fed PR diets (Fontana et al., 2016; Laeger et al., 2014).”
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“This is In mice, multiple manipulations lead to a significant increase in FGF21 levels, including fasting and consumption of a ketogenic diet [3,4], protein insufficiency, and amino acid deprivation [5].”
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“The engineered FGF21, FGF21(1-171)-WD22, is functionally indistinguishable from native FGF21 in terms of signaling activation, receptor binding specificity, and induction of adipose glucose uptake, but has increased potency with the more tolerant C-terminal modification.”
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Impact of dietary carbohydrate type and protein–carbohydrate interaction on metabolic health
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- 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 · 2012: 1
- 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 › 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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