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.
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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]
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Lamming, D. W., & Salmon, A. B. (2019) · The Journals of Gerontology Series A · doi:10.1093/gerona/glz212 · Cited by 6
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Gut Microbiota Modulates Fgf21 Expression and Metabolic Phenotypes Induced by Ketogenic Diet
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“FGF21 is an endocrine signal of protein restriction [31].”
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“Under these conditions, FGF21 production is upregulated specifically in the liver following activation of the integrated stress response [103–105].”
InfluentialUPRmt-regulated mitokines: novel strategies for myocardial injury repair
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“34,35,57,68 Multiple groups have shown that FGF21 is required for many metabolic effects of PR, including increased food intake, reduced body weight, increased energy expenditure, and extended lifespan.”
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“24,25 Notably, a previous report suggested that the ERK1/2 signaling pathway is governed by FGF21.”
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“25,50 FGF21 is an insulin-sensitizing hormone produced by the liver in response to nutrient 73,74 Similar with low protein and high carbohydrate composition and that the expression Atf5 is most correlated with dietary-induced expression of FGF21.”
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Self-citationBibliometric analysis of fibroblast growth factor 21 research over the period 2000 to 2021
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“, 2022), can induce FGF-21 expression through endoplasmic stress response (Laeger et al., 2014), FGF-21 was considered a stress-related factor and opened a novel aspect to comprehend the metabolic effects of FGF-21.”
BackgroundMunoz, M. D., Zamudio, A., McCann, M. A., Gil, V., Xu, P., & Liew, C. W. (2023) · Scientific Reports · doi:10.1038/s41598-023-37482-6 · Cited by 5
“Previous studies demonstrated that LPD-induced metabolic benefits are at least partially mediated by FGF21 27,28,32 .”
Trautman, M. E., Narasimhan, A., Adrian, A. E., Kumar, A., Green, C. L., Soto-Palma, C., Henpita, C., Camell, C. D., Morrow, C. S., Yeh, C., et al. (2021) · GeroScience · doi:10.1007/s11357-021-00479-y · Cited by 4
Die Leberverfettung der Milchkuh: Teil 1
Märtens, H. (2023) · Tierärztliche Praxis Ausgabe G Großtiere / Nutztiere · doi:10.1055/a-2066-2596 · Cited by 4
“Die Entkoppelung der GH-IGF-1 Achse bei Mäusen führt mit Ausnahme der Glukose- und Insulinkonzentration zu hormonellen und metabolischen Veränderungen, die bei Kühen mit einer Fettleber beschrieben werden wie z.”
BackgroundInfluentialGodoy-Lugo, J. A., Young, K. E., Vaddi, P., Batamack, Y., Aldridge, J., Fernandez‐Kim, S. O., Albarado, D. C., Burke, S. J., Stephens, J. M., Morrison, C. D., et al. (2025) · GeroScience · doi:10.1007/s11357-025-01853-w · Cited by 4
“…Liver is altered in response to nutrient cues, several years ago, it was discovered that the Liver-derived hormone fibroblast growth factor 21 (FGF21) serves as an effector signal of protein restriction, as such, the deletion of FGF21 blocks adaptive metabolic responses to PR in young mice [14].”
Self-citationEnergy restriction drives adipose tissue remodeling and thermogenic adaptation
Mısırlıoğlu, P. E. (2025) · Discover Medicine · doi:10.1007/s44337-025-00535-y · Cited by 3
Spann, R. A., Kim, S. Q., Khan, M. S. H., Albarado, D. A., Fernandez‐Kim, S. O., Berthoud, H., McDougal, D. H., Münzberg, H., He, Y., Yu, S., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117218 · Cited by 4
Self-citationProtein Decoys, Alcohol, and Energy Intake: Testing a Mechanistic‐Ecological Model
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Szczepańska, E., Glinicki, P., Zgliczyński, W., Slowinska-Srzednicka, J., Jastrzębska, H., & Gietka‐Czernel, M. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.900034 · Cited by 3
“Serum FGF21 is generated primarily in the liver (10) under nutritional stress stimuli like starvation (11, 12) or a lipotoxic diet (12 – 15), but also increased mitochondrial and endoplasmic reticulum stress (16, 17).”
Zhang, J., Zhang, X., Li, P., Liu, Y., Zhang, C., Lu, M., Gao, L., Song, Z., Sun, H., & Qiu, J. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70039 · Cited by 3
“20,33,35,36 Third, while murine studies yield valuable insights, the extrapolation of these findings to human physiology warrants investigation.”
Maldonado-Cedillo, B. G., Dı́az-Ruiz, A., Montes, S., Galván‐Arzate, S., Rı́os, C., Campos, V., Alcaraz-Zubeldia, M., & Díaz-Cintra, S. Y. (2015) · Nutritional Neuroscience · doi:10.1179/1476830515y.0000000003 · Cited by 3
Glycolysis Inhibition: The Gift of GAB(A)
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Matye, D. J., Wang, H., Wang, Y., Xiong, L., & Li, T. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00353.2024 · Cited by 3
The Influence of Kidney Disease on Protein and Amino Acid Metabolism
Workeneh, B., & Mitch, W. E. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-391934-2.00001-1 · Cited by 3
Identificación del fenotipo ahorrador para la personalización del manejo del sobrepeso y la obesidad
Fernando Carrasco, N., & Navarro, G. N. C. (2022) · Revista Médica Clínica Las Condes · doi:10.1016/j.rmclc.2022.03.006 · Cited by 6
Stevanović, D., Hebert, A. J., Desai, B. N., Singhal, G., Adams, A. C., Flier, J. S., & Maratos–Flier, E. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.27.921361 · Cited by 3
“Regulation of expression is also complex, and multiple transcription factors have been implicated in driving changes in responses to dietary challenges, such as fasting, ketogenic diets, lipotoxic diets, protein restriction, and cold exposure [9–15].”
BackgroundFluctuations of serum fibroblast growth factor-21 levels in prolonged fasting in male adults
Ağaçdiken, A., & Göktaş, Z. (2023) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2023.06.024 · Cited by 3
Lyon, A., Agius, T., MacArthur, M. R., Kiesworo, K., Stavart, L., Allagnat, F., Mitchell, S. J., Riella, L. V., Uygun, K., Yeh, H., et al. (2024) · iScience · doi:10.1016/j.isci.2024.111256 · Cited by 2
Zhang, X., Li, Z., Wang, S., & Chen, Y. (2025) · Nutrients · doi:10.3390/nu17071179 · Cited by 2
“In humans, Fgf21 expression can be induced by starvation [15,16], protein restriction [17], high-fructose or carbohydrate intake [18,19], and alcohol consumption [20,21].”
de Luis, D., Primo, D., Izaola, O., & Gómez, J. J. L. (2025) · Nutrición Hospitalaria · doi:10.20960/nh.05792 · Cited by 2
Torres‐Oteros, D., Nicola‐Llorente, M., Sanz‐Lamora, H., Pérez‐Martí, A., Marrero, P. F., Canudas, S., Haro, D., & Relat, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms27010194 · Cited by 2
“Typically, hepatic FGF21 production is induced under metabolic challenges such as fasting, high-fat or low-protein diets, and metabolic syndromes, including MAFLD [4,6,46–48].”
Maternal BCAA overnutrition programs persistent dysglycemia in lean adult offspring
TZENG, J., Ferrer, I., & Lorenzo, D. N. (2026) · Molecular Metabolism · doi:10.1016/j.molmet.2026.102331 · Cited by 2
“G), and reduced serum levels of fibroblast growth factor 21 (FGF21), a liver-derived hormone that enhances adipose glucose uptake and systemic insulin sensitivity [34], which production and secretion is increased by BCAA restriction [24,35 — 37] (Figure 1H).”
Lail, H. L., Lawrence, R. C., Pinheiro, F., Price, E., & Wanders, D. (2026) · PLoS ONE · doi:10.1371/journal.pone.0343503 · Cited by 2
Lin, Y., Claflin, K. E., Aklan, İ., Morgan, D. A., Sullivan, A. I., Rudolph, M. C., Rahmouni, K., & Potthoff, M. J. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117093 · Cited by 3
“27,28 However, the underlying mechanisms remain insufficiently defined.”
Ozaki‐Masuzawa, Y., Kosaka, H., Abiru, R., Toda, Y., Kawabata, K., Nagata, M., Hara, S., Konishi, M., Itoh, N., Hosono, T., et al. (2021) · Bioscience Biotechnology and Biochemistry · doi:10.1093/bbb/zbab030 · Cited by 2
Growth hormone resistance induced by amino acid deprivation in fao cells is independent of FGF21
Saito, M., Nishi, H., Takahashi, S., Hakuno, F., & Miyata, I. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.149811 · Cited by 2
Jain, U., Srivastava, P., Sharma, A., Sinha, S., & Johari, S. (2024) · Current Diabetes Reviews · doi:10.2174/0115733998265915231116043813 · Cited by 3
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Daily Complementary Feeding With Eggs Improves Fibroblast Growth Factor 21 in Infants
Nakiranda, R., Malan, L., Ricci, H., Kruger, H. S., Nienaber, A., Visser, M., Ricci, C., Faber, M., & Smuts, C. M. (2024) · Maternal and Child Nutrition · doi:10.1111/mcn.13782 · Cited by 2
“FGF21 levels increase in response to reduced protein intake (Kliewer and Mangelsdorf 2019; Laeger et al. 2014; Potthoff et al. 2009).”
Kiyama, G., Nakashima, K., Shimada, K., Murono, N., Kakihana, W., Imai, H., Inoue, M., & Hirai, T. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112078 · Cited by 2
Fibroblast growth factor 21: new insights from human studies
Hansen, J. S., & Plomgaard, P. (2016) · Cardiovascular Endocrinology · doi:10.1097/xce.0000000000000084 · Cited by 2
Protein appetite drives macronutrient-related differences in ventral tegmental area neural activity
(21471335), G. C., (8373876), F. N., Peters, K. Z., (7733501), J. A.-S., (21471338), E. S., & (8373882), J. M. (2025) · Figshare · Cited by 2
Gehring, J., Azzout‐Marniche, D., Chaumontet, C., Gaudichon, C., & Even, P. C. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00204.2021 · Cited by 2
Meal-to-meal and day-to-day macronutrient variation in an ad libitum vending food paradigm
de Baca, T. C., Piaggi, P., Gluck, M. E., Krakoff, J. A., & Votruba, S. B. (2022) · Appetite · doi:10.1016/j.appet.2022.105944 · Cited by 2
Patel, S., Haider, A., Álvarez-Guaita, A., Bidault, G., Moustafa, J. S. E.-S., Guiu‐Jurado, E., Tadross, J. A., Warner, J., Harrison, J., Virtue, S., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.08.495255 · Cited by 2
Persistent Behavioral and Physiological Effects of Dietary Protein RestrictionPreprint
Soto, P. L., & Morrison, C. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.04.583396 · Cited by 2
Self-citationDietary Insulinogenic Amino Acid Restriction Improves Glucose Metabolism in a Neonatal Piglet Model
Gorton, M. W., Goodarzi, P., Lei, X., Anderson, M. C., Habibi, M., Wilson, N. F., & Pezeshki, A. (2025) · Nutrients · doi:10.3390/nu17101675 · Cited by 1
“In support of our findings, previous studies from our laboratory and others have shown that AA restriction [27,100,122], BCAA restriction [32,44,123], and protein dilution [96,99,124–126] increase either blood FGF-21 concentration or hepatic FGF-21 transcript in rodent models.”
Ramne, S., Seco, T. D. D. C., Kuentzel, K. B., Grevengoed, T. J., Hjerresen, J. P., Möritz, T., Hansen, T. F., Raben, A., & Grarup, N. (2025) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00265.2025 · Cited by 2
FGF‐21 and 8‐OHdG Biomarkers in Drug‐Naïve Children With Autism Spectrum Disorder
Baraúna, S., Sylvestre, G., & Quagliato, L. A. (2025) · International Journal of Developmental Neuroscience · doi:10.1002/jdn.70069 · Cited by 1
Investigation of the effects and mechanisms of endogenous deletion of FGF21 on cognitive functions
Jiang, Z., Tian, X., Sun, M., Yuan, H.-Z.-X., Xiang, S.-R., Zhang, H.-F., Zhang, J.-P., Cui, L.-Y., & Wang, W. (2025) · Physiology & Behavior · doi:10.1016/j.physbeh.2025.115174 · Cited by 1
Shi, F., Yang, Z., Zhang, L., Zou, D., Yu, J., Guo, N., Ren, S., Tang, X., Gu, C. J., Xu, R., et al. (2025) · Microbiome · doi:10.1186/s40168-025-02233-4 · Cited by 1
“These adaptive metabolic stress responses are driven by hepatic fibroblast growth factor 21 (FGF21), an endocrine hormone induced by a LP diet [15–18].”
Vagal sensory neurons encode internal protein status to guide eating
Yang, M., de Araujo, A., Shakir, J., Braga, I., Méndez‐Hernández, R., Tofani, G. S. S., Bali, A., de Lartigue, J., Song, H., McCutcheon, J. E., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102303 · Cited by 1
“Deletion of FGF21 or its co-receptor beta Klotho (Klb) from glutamatergic neurons abolishes the protein preference normally observed during protein restriction, suggesting that FGF21 is sufficient to detect or respond to protein need [13,29,32].”
InfluentialSelf-citationDietary strategies to counter obesity-accelerated aging: Enhancing health-span and longevity
Rao, P. P. (2026) · Obesity Medicine · doi:10.1016/j.obmed.2026.100702 · Cited by 1
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“This microbial shift serves as an upstream trigger for the robust upregulation of hepatic FGF21, a pleiotropic hepatokine that coordinates energy expenditure, glucose-lipid homeostasis, and mac-ronutrient preference [103–105].”
Lifestyle factors moderate emotion–gait coupling in young adults
Wadsworth, D. D., Adlou, B., Grace, J. L., Kosek, J., Wilburn, C. M., & Weimar, W. H. (2026) · Experimental Brain Research · doi:10.1007/s00221-026-07321-x · Cited by 1
“Furthermore, protein intake influences circulating levels of fibroblast growth factor 21 (FGF21), a hormone that coor - dinates feeding behavior and metabolism during periods of altered protein consumption (Laeger et al. 2014 ).”
Grandl, G., König, A., Metzger, F., Liśkiewicz, A., Hefele, T., Nason, S., Novikoff, A., Al-Refaie, N., Rahman, M. A., Khalil, A., et al. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.05.011 · Cited by 2
Macronutrient mixtures and interactions in health and disease
Simpson, S. J., Couteur, D. G. L., Small, L., Brandon, A. E., & Raubenheimer, D. (2026) · Nature Reviews Endocrinology · doi:10.1038/s41574-026-01266-5 · Cited by 1
Metadata
- Authors
- Laeger, T., Henagan, T. M., Albarado, D. C., Redman, L. M., Bray, G. A., Noland, R. C., Münzberg, H., Hutson, S. M., Gettys, T. W., Schwartz, M. W., & Morrison, C. D.
- Affiliations
- Pennington Biomedical Research Center (US)
- Virginia Tech (US)
- University of Washington (US)
- Corresponding author
- Morrison, Christopher D.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-08-18
- Volume
- 124
- Issue
- 9
- Pages
- 3913-3922
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4153701
- OpenAlex
- W2170065584
- Cited by
- 593
- References
- 59
- Citations by year
- 2026: 42 · 2025: 58 · 2024: 47 · 2023: 48 · 2022: 58 · 2021: 54 · 2020: 43 · 2019: 51 · 2018: 46 · 2017: 56 · 2016: 51 · 2015: 34 · 2014: 4
- FWCI
- 19.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (LA 3042/2-1)
- National Institutes of Health
- Nutrition Obesity Research Center, University of North Carolina (#P30DK072476)
- National Institute of General Medical Sciences (P20GM103528, P30GM118430)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101997, R01DK096311, R01DK081563, P30DK035816, P30DK017047, T32DK064584, P30DK072476, R01DK083042)
- National Center for Research Resources (P20RR021945)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- FGF21, protein restriction, low-protein diet, hormone signaling, eIF2α phosphorylation, GCN2, starvation, ketogenic diet, dietary intake, energy expenditure, body weight, metabolic adaptation
- MeSH terms
- Animals, Dietary Proteins, Energy Metabolism, Fibroblast Growth Factors, Male, Mice, Inbred C57BL, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Caloric Restriction, PPAR alpha, Mice, Rats, Diet, Ketogenic
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