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FGF21 is an endocrine signal of protein restriction
Open accessAbstract
Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.
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In the citing paper
“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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“Protein restriction increases energy expenditure in a FGF21-dependent manner in mice (167).”
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“Mice lacking FGF21 are refractory to diet-induced energy expenditure (12) and prone to developing NASH (8, 13, 14).”
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“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…”
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“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…”
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“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 140
“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
“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 137
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
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Xiao, F., & Guo, F. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101393 · Cited by 142
“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
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Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans
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“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
Regulation of longevity by FGF21: interaction between energy metabolism and stress responses
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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 119
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FGF21 activates AMPK signaling: impact on metabolic regulation and the aging process
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“[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 123
“Nutritional stress, in particular protein restriction (Laeger et al., 2014), increases FGF21 transcription in and release from liver (BonDurant & Potthoff, 2018).”
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“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 118
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“…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,…”
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“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 114
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
“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 102
FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases
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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
“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
“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
“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
Fibroblast growth factor 21 night watch: advances and uncertainties in the field
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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
FGF21 and the physiological regulation of macronutrient preference
Hill, C. M., Qualls-Creekmore, E., Berthoud, H.-R., Soto, P., Yu, S., McDougal, D. H., Münzberg, H., & Morrison, C. D. (2020) · Endocrinology · doi:10.1210/endocr/bqaa019 · Cited by 99
Self-citationHill, C. M., Laeger, T., Albarado, D. C., McDougal, D. H., Berthoud, H.-R., Münzberg, H., & Morrison, C. D. (2017) · Scientific Reports · doi:10.1038/s41598-017-07498-w · Cited by 97
Integrated stress response stimulates FGF21 expression: Systemic enhancer of longevity
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.08.009 · Cited by 100
“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].”
BackgroundInfluentialKitada, M., Ogura, Y., Suzuki, T., Sen, S., Lee, S. M., Kanasaki, K., Kume, S., & Koya, D. (2016) · Diabetologia · doi:10.1007/s00125-016-3925-4 · Cited by 97
Metabolic Determinants of Weight Gain in Humans
Piaggi, P. (2019) · Obesity · doi:10.1002/oby.22456 · Cited by 100
“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
Menezes, L. F., & Germino, G. G. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0183-y · Cited by 96
The biology of human overfeeding: A systematic review
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Self-citationHenriksson, E., & Andersen, B. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601349 · Cited by 97
“In response to protein restriction FGF21 is required to increase food intake (in order to meet the protein demand) and energy expenditure (EE) (68).”
BackgroundInfluentialSøberg, S., Andersen, E. S., Dalsgaard, N. B., Jarlhelt, I., Hansen, N. L., Hoffmann, N., Vilsbøll, T., Chenchar, A., Jensen, M., Grevengoed, T. J., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.03.010 · Cited by 94
“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
Bröer, S. (2023) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-061121-094344 · Cited by 105
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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].”
BackgroundFibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges
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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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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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