Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2
Open accessAbstract
FGF21 contributes to the metabolic response to dietary protein restriction, and prior data implicate GCN2 as the amino acid sensor linking protein restriction to FGF21 induction. Here, we demonstrate the persistent and essential role of FGF21 in the metabolic response to protein restriction. We show that Fgf21 KO mice are fully resistant to low protein (LP)-induced changes in food intake, energy expenditure (EE), body weight gain, and metabolic gene expression for 6 months. Gcn2 KO mice recapitulate this phenotype, but LP-induced effects on food intake, EE, and body weight subsequently begin to appear after 14 days on diet. We show that this delayed emergence of LP-induced metabolic effects in Gcn2 KO mice coincides with a delayed but progressive increase of hepatic Fgf21 expression and blood FGF21 concentrations over time. These data indicate that FGF21 is essential for the metabolic response to protein restriction but that GCN2 is only transiently required for LP-induced FGF21.
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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 [124]
The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to induction of hepatic and circulating FGF21.
“The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to the induction of hepatic and circulating levels of FGF21 (24, 68, 72).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [72]
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 [72]
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 [160]
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 [160]
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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 · see citing works
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 · see citing works
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 · see citing works
Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans
Lee, P., Linderman, J. D., Smith, S., Brychta, R. J., Wang, J., Idelson, C., Perron, R. M., Werner, C. D., Phan, G. Q., Kammula, U. S., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2013.12.017 · Cited by 802 · see citing works
Potthoff, M. J., Inagaki, T., Satapati, S., Ding, X., He, T., Goetz, R., Mohammadi, M., Finck, B. N., Mangelsdorf, D. J., Kliewer, S. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904187106 · Cited by 704 · see citing works
FGF21 is an endocrine signal of protein restriction
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., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74915 · Cited by 593 · cited 10× · 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-citationObesity: the protein leverage hypothesis
Simpson, S. J., & Raubenheimer, D. (2005) · Obesity Reviews · doi:10.1111/j.1467-789x.2005.00178.x · Cited by 591 · see citing works
Wek, S. A., Zhu, S., & Wek, R. C. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.8.4497 · Cited by 487 · see citing works
Endocrine fibroblast growth factors 15/19 and 21: from feast to famine
Potthoff, M. J., Kliewer, S. A., & Mangelsdorf, D. J. (2012) · Genes & Development · doi:10.1101/gad.184788.111 · Cited by 442 · see citing works
The GCN2 eIF2α Kinase Is Required for Adaptation to Amino Acid Deprivation in Mice
Zhang, P., McGrath, B. C., Reinert, J., Olsen, D. S., Li, L., Gill, S., Wek, S. A., Vattem, K. M., Wek, R. C., Kimball, S. R., et al. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.19.6681-6688.2002 · Cited by 439 · see citing works
Guo, F., & Cavener, D. R. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.01.001 · Cited by 301 · see citing works
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
Leucine Deprivation Increases Hepatic Insulin Sensitivity via GCN2/mTOR/S6K1 and AMPK Pathways
Xiao, F., Huang, Z., Li, H., Yu, J., Wang, C., Chen, S., Meng, Q., Cheng, Y., Gao, X., Li, J., et al. (2011) · Diabetes · doi:10.2337/db10-1246 · Cited by 286 · see citing works
The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue
Adams, A. C., Yang, C., Coskun, T., Cheng, C. C., Gimeno, R. E., Luo, Y., & Kharitonenkov, A. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2012.08.007 · Cited by 266 · see citing works
Hamanaka, R. B., Bennett, B. S., Cullinan, S. B., & Diehl, J. A. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-03-0268 · Cited by 250 · see citing works
Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation
De Sousa-Coelho, A. L., Marrero, P. F., & Haro, D. (2012) · Biochemical Journal · doi:10.1042/bj20111748 · Cited by 246 · see citing works
Macronutrient balance, reproductive function, and lifespan in aging mice
Solon-Biet, S. M., Walters, K. A., Simanainen, U. K., McMahon, A. C., Ruohonen, K., Ballard, J. W. O., Raubenheimer, D., Handelsman, D. J., Le Couteur, D. G., & Simpson, S. J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1422041112 · Cited by 243 · see citing works
Anthony, T. G., McDaniel, B. J., Reinert, R. B., McGrath, B. C., Cavener, D. R., McNurlan, M. A., & Wek, R. C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m404559200 · Cited by 225 · see citing works
Hasek, B. E., Stewart, L. K., Henagan, T. M., Boudreau, A., Lenard, N. R., Black, C. L., Shin, J., Huypens, P., Malloy, V. L., Plaisance, E. P., et al. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00837.2009 · Cited by 218 · see citing works
Self-citationCentral Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice
Douris, N., Stevanovic, D. M., Fisher, F. M., Cisu, T. I., Chee, M. J., Nguyen, N. L., Zarebidaki, E., Adams, A. C., Kharitonenkov, A., Flier, J. S., et al. (2015) · Endocrinology · doi:10.1210/en.2014-2001 · Cited by 215 · see citing works
Pharmacologic Effects of FGF21 Are Independent of the “Browning” of White Adipose Tissue
Véniant, M. M., Sivits, G., Helmering, J., Komorowski, R., Lee, J., Fan, W., Moyer, C., & Lloyd, D. J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.04.019 · Cited by 204 · see citing works
Inventing new medicines: The FGF21 story
Kharitonenkov, A., & Adams, A. C. (2014) · Molecular Metabolism · doi:10.1016/j.molmet.2013.12.003 · Cited by 198 · see citing works
Protein leverage and energy intake
Gosby, A. K., Conigrave, A. D., Raubenheimer, D., & Simpson, S. J. (2014) · Obesity Reviews · doi:10.1111/obr.12131 · Cited by 196 · see citing works
Amino acids inhibit <i>Agrp</i> gene expression via an mTOR-dependent mechanism
Morrison, C. D., Xi, X., White, C. L., Ye, J., & Martin, R. J. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00675.2006 · Cited by 183 · see citing works
Self-citationFibroblast growth factor 21 is induced by endoplasmic reticulum stress
Schaap, F. G., Kremer, A. E., Lamers, W. H., Jansen, P. L. M., & Gaemers, I. C. (2012) · Biochimie · doi:10.1016/j.biochi.2012.10.019 · Cited by 164 · see citing works
Discrete Aspects of FGF21 In Vivo Pharmacology Do Not Require UCP1
Samms, R. J., Smith, D. P., Cheng, C. C., Antonellis, P. P., Perfield, J. W., Kharitonenkov, A., Gimeno, R. E., & Adams, A. C. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.04.046 · Cited by 154 · see citing works
A 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
Hasek, B. E., Boudreau, A., Shin, J., Feng, D., Hulver, M. W., Van, N. T., Laque, A., Stewart, L. K., Stone, K. P., Wanders, D., et al. (2013) · Diabetes · doi:10.2337/db13-0501 · Cited by 136 · see citing works
Self-citationMechanisms of thermogenesis induced by low protein diets
Rothwell, N. J., Stock, M. J., & Tyzbir, R. S. (1983) · Metabolism · doi:10.1016/0026-0495(83)90190-7 · Cited by 124 · see citing works
FGF21 mediates the lipid metabolism response to amino acid starvation
De Sousa-Coelho, A. L., Relat, J., Hondares, E., Pérez-Martí, A., Ribas, F., Villarroya, F., Marrero, P. F., & Haro, D. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m033415 · Cited by 123 · see citing works
Kim, K. H., Jeong, Y. T., Kim, S. H., Jung, H. S., Park, K. S., Lee, H.-Y., & Lee, M.-S. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.09.026 · Cited by 112 · see citing works
Geometric analysis of macronutrient selection in the rat
SIMPSON, S. J., & RAUBENHEIMER, D. (1997) · Appetite · doi:10.1006/appe.1996.0077 · Cited by 110 · 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
Self-citationHomeostatic regulation of protein intake: in search of a mechanism
Morrison, C. D., Reed, S. D., & Henagan, T. M. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00609.2011 · Cited by 99 · see citing works
Self-citationProtein selection, food intake, and body composition in response to the amount of dietary protein
White, B. D., Porter, M. H., & Martin, R. J. (2000) · Physiology & Behavior · doi:10.1016/s0031-9384(99)00232-2 · Cited by 91 · see citing works
Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., Mendoza, T. M., Mynatt, R. L., & Gettys, T. W. (2015) · The FASEB Journal · doi:10.1096/fj.14-270348 · Cited by 88 · see citing works
Self-citationRothwell, N., & Stock, M. J. (1987) · Journal of NutriLife · doi:10.1093/jn/117.10.1721 · Cited by 78 · see citing works
Neurobiology of Nutrition and Obesity
Morrison, C. D., & Berthoud, H. (2007) · Nutrition Reviews · doi:10.1301/nr.2007.dec.517-534 · Cited by 65 · see citing works
Self-citationLaeger, T., Reed, S. D., Henagan, T. M., Fernandez, D. H., Taghavi, M., Addington, A. K., Münzberg, H., Martin, R. J., Hutson, S. M., & Morrison, C. D. (2014) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00116.2014 · Cited by 63 · see citing works
Self-citationRemodeling of lipid metabolism by dietary restriction of essential amino acids
Anthony, T. G., Morrison, C. D., & Gettys, T. W. (2013) · Diabetes · doi:10.2337/db12-1613 · Cited by 52 · see citing works
Self-citationWilson, 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 · see citing works
Bernardo, B. L., Lu, M. M., Bandyopadhyay, G. K., Li, P., Zhou, Y., Huang, J. S., Levin, N., Tomás, E., Calle, R. A., Erion, D. M., et al. (2015) · Scientific Reports · doi:10.1038/srep11382 · Cited by 46 · see citing works
Dudek, S. M., & Semenkovich, C. F. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.49.29323 · Cited by 40 · see citing works
Flagged first, then by citations
1 of the 44 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Molecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · 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
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
Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311 · see citing works
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
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
Self-citationFibroblast 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
Defining 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
Self-citationDietary regulation in health and disease
Wu, Q., Gao, Z., Yu, X., & Wang, P. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01104-w · Cited by 182 · see citing works
Fibroblast 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
Desai, 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 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
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
Amino acid is a major carbon source for hepatic lipogenesis
Liao, Y., Chen, Q., Liu, L., Huang, H., Sun, J., Bai, X., Jin, C., Li, H., Sun, F., Xiao, X., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.10.001 · Cited by 122 · 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
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
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
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
Self-citationFGF21 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 · see citing works
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 · see citing works
Self-citationMetabolic Determinants of Weight Gain in Humans
Piaggi, P. (2019) · Obesity · doi:10.1002/oby.22456 · Cited by 96 · see citing works
Intestinal Amino Acid Transport and Metabolic Health
Bröer, S. (2023) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-061121-094344 · Cited by 96 · see citing works
Regulation of metabolic health by essential dietary amino acids
Green, C. L., & Lamming, D. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.07.004 · Cited by 88 · see citing works
Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges
Martínez‐Garza, Ú., Torres‐Oteros, D., Yarritu, A., Marrero, P. F., Haro, D., & Relat, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194692 · Cited by 87 · see citing works
Yin, J., Li, Y., Zhu, X., Han, H. L., Ren, W., Chen, S., Bin, P., Liu, G., Huang, X., Fang, R., et al. (2017) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.7b02746 · Cited by 83 · see citing works
Central 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 81 · see citing works
Wu, 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 · see citing works
Haro, D., Marrero, P., & Relat, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061386 · Cited by 56 · see citing works
Rader, 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 · see citing works
Trautman, M. E., Richardson, N. E., & Lamming, D. W. (2022) · Aging Cell · doi:10.1111/acel.13626 · Cited by 67 · see citing works
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 · see citing works
Brown-Borg, H. M., & Buffenstein, R. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.08.007 · Cited by 70 · see citing works
Spann, R. A., Morrison, C. D., & den Hartigh, L. J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.802541 · Cited by 75 · see citing works
Self-citationHomeostatic 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 · see citing works
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 · see citing works
Maida, 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 · see citing works
Sex 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 · see citing works
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 64 · see citing works
Methionine restriction alleviates age-associated cognitive decline via fibroblast growth factor 21
Ren, B., Wang, L., Shi, L. S., Jin, X., Liu, Y., Liu, R. H., Yin, F., Cadenas, E., Dai, X., Liu, Z., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101940 · Cited by 62 · see citing works
Laeger, T., Baumeier, C., Wilhelmi, I., Würfel, J., Kamitz, A., & Schürmann, A. (2017) · Diabetologia · doi:10.1007/s00125-017-4389-x · Cited by 59 · see citing works
Self-citationGlucagon'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 76 · see citing works
Cross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases
Wu, D., Wang, H., Xie, L., & Hu, F. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.908868 · Cited by 61 · see citing works
Allard, C., Bonnet, F., Xu, B., Coons, L. A., Albarado, D. C., Hill, C. M., Fagherazzi, G., Korach, K. S., Levin, E. R., Lefante, J. J., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.02.002 · Cited by 58 · see citing works
Self-citationPérez‐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 · see citing works
Pettit, 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 54 · see citing works
Self-citationTrevino-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 · see citing works
Martin, 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 51 · see citing works
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 51 · see citing works
Yuan, F., Jiang, H., Yin, H., Jiang, X., Jiao, F., Chen, S., Ying, H., Chen, Y., Zhai, Q., & Guo, F. (2020) · Nature Communications · doi:10.1038/s41467-020-16662-2 · Cited by 51 · see citing works
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 50 · see citing works
Chalvon‐Demersay, T., Blachier, F., Tomé, D., & Blais, A. (2017) · Frontiers in Nutrition · doi:10.3389/fnut.2017.00005 · Cited by 50 · see citing works
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 · see citing works
Flippo, 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 · see citing works
Mu, W., Vanhoosier, E., Elks, C. M., & Grant, R. W. (2018) · Nutrients · doi:10.3390/nu10070918 · Cited by 48 · see citing works
50 years of research on α-amino-β-methylaminopropionic acid (β-methylaminoalanine)
Nunn, P. B. (2017) · Phytochemistry · doi:10.1016/j.phytochem.2017.10.002 · Cited by 46 · see citing works
ChREBP-Knockout Mice Show Sucrose Intolerance and Fructose Malabsorption
Kato, T., Iizuka, K., Takao, K., Horikawa, Y., Kitamura, T., & Takeda, J. (2018) · Nutrients · doi:10.3390/nu10030340 · Cited by 46 · see citing works
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 41 · see citing works
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 · see citing works
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 44 · see citing works
Xu, X., Krumm, C. S., So, J., Bare, C. J., Holman, C. D., Gromada, J., Cohen, D. E., & Lee, A. (2018) · Hepatology · doi:10.1002/hep.30060 · Cited by 43 · see citing works
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 43 · see citing works
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 · see citing works
The regulation of healthspan and lifespan by dietary amino acids
Babygirija, R., & Lamming, D. (2021) · Translational Medicine of Aging · doi:10.1016/j.tma.2021.05.001 · Cited by 31 · see citing works
Forney, L. A., Stone, K. P., Gibson, A. N., Vick, A. M., Sims, L. C., Fang, H., & Gettys, T. W. (2020) · Obesity · doi:10.1002/oby.22721 · Cited by 39 · see citing works
Self-citationProtein metabolism and related body function: mechanistic approaches and health consequences
Tomé, D., Benoit, S., & Azzout‐Marniche, D. (2020) · Proceedings of The Nutrition Society · doi:10.1017/s0029665120007880 · Cited by 39 · see citing works
Hua, L., Zhuo, Y., Jiang, D., Li, J., Huang, X., Yingguo, Z., Li, Z., Yan, L., Jin, C., Jiang, X., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201800240r · Cited by 37 · see citing works
Javed, K., & Bröer, S. (2019) · Nutrients · doi:10.3390/nu11092024 · Cited by 37 · see citing works
Jonsson, W. O., Margolies, N., Mirek, E. T., Zhang, Q., Linden, M. A., Hill, C. M., Link, C., Bithi, N., Zalma, B. A., Levy, J. L., et al. (2020) · Journal of Nutrition · doi:10.1093/jn/nxaa396 · Cited by 35 · see citing works
Self-citationLow Protein Diets and Energy Balance: Mechanisms of Action on Energy Intake and Expenditure
Pezeshki, A., & Chelikani, P. K. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.655833 · Cited by 35 · see citing works
Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity
Ryu, S., Spadaro, O., Sidorov, S., Lee, A. H., Caprio, S., Morrison, C. D., Smith, S. R., Ravussin, É., Shchukina, I., Artyomov, M. N., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci169173 · Cited by 34 · see citing works
Self-citationThe link among microbiota, epigenetics, and disease development
El-Sayed, A., Aleya, L., & Kamel, M. S. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-021-13862-1 · Cited by 36 · see citing works
Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis
Khan, M. S. H., Spann, R. A., Münzberg, H., Yu, S., Albaugh, V. L., He, Y., Berthoud, H., & Morrison, C. D. (2021) · Nutrients · doi:10.3390/nu13114103 · Cited by 35 · see citing works
Self-citationZapata, R. C., Singh, A., Pezeshki, A., Avirineni, B. S., Patra, S., & Chelikani, P. K. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900088 · Cited by 33 · see citing works
Nicolaisen, T. S., Lyster, A. E., Sjøberg, K. A., Haas, D. T., Voldstedlund, C. T., Lundsgaard, A., Jensen, J. K., Madsen, E. M., Nielsen, C. K., Bloch‐Ibenfeldt, M., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01236-7 · Cited by 36 · see citing works
FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk
CHAFFIN, A. T. B., Larson, K. R., Huang, K.-P., Wu, C.-T., Nadejda, G., Fang, Y., Jayakrishnan, D., Sauza, K. A. S., Sims, L. C., Mohajerani, N., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.155848 · Cited by 31 · see citing works
A nutrigeroscience approach: Dietary macronutrients and cellular senescence
Calubag, M. F., Robbins, P. D., & Lamming, D. W. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.07.025 · Cited by 32 · see citing works
Alonge, K. M., Meares, G. P., & Hillgartner, F. B. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.762922 · Cited by 31 · see citing works
Wade, H., Pan, K., & Su, Q. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000771 · Cited by 31 · see citing works
Roh, E., Hwang, S. Y., Yoo, H. J., Baik, S. H., Cho, B., Park, Y. S., Kim, H. J., Lee, S., Kim, B., Jang, H. C., et al. (2021) · Age and Ageing · doi:10.1093/ageing/afab178 · Cited by 31 · see citing works
Hua, L., Li, J., Feng, B., Jiang, D., Jiang, X., Luo, T., Che, L., Xu, S., Lin, Y., Fang, Z., et al. (2020) · Endocrinology · doi:10.1210/endocr/bqaa244 · Cited by 30 · see citing works
Burke, S. J., Batdorf, H. M., Martin, T. M., Burk, D. H., Noland, R. C., Cooley, C. R., Karlstad, M. D., Johnson, W. D., & Collier, J. J. (2018) · Obesity · doi:10.1002/oby.22217 · Cited by 28 · see citing works
Self-citationDommerholt, M. B., Blankestijn, M., Vieira‐Lara, M. A., van Dijk, T. H., Wolters, H., Koster, M. H., Gerding, A., van Os, R. P., Bloks, V. W., Bakker, B. M., et al. (2020) · FEBS Journal · doi:10.1111/febs.15604 · Cited by 27 · see citing works
Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism
Paulo, E., Zhang, Y., Masand, R., Huynh, T. L., Seo, Y., Swaney, D. L., Soucheray, M., Stevenson, E. J., Jimenez‐Morales, D., Krogan, N. J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109742 · Cited by 26 · see citing works
Forney, L. A., Stone, K. P., Wanders, D., & Gettys, T. W. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.12.002 · Cited by 28 · see citing works
Self-citationKitada, M., Ogura, Y., Suzuki, T., Monno, I., Kanasaki, K., Watanabe, A., & Koya, D. (2018) · Nutrition & Metabolism · doi:10.1186/s12986-018-0255-1 · Cited by 27 · see citing works
Khan, M. S. H., Kim, S. Q., Ross, R. C., Corpodean, F., Spann, R. A., Albarado, D. A., Fernandez‐Kim, S. O., Clarke, B. A., Berthoud, H., Münzberg, H., et al. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102068 · Cited by 28 · see citing works
Self-citationMuscle-specific deletion of BDK amplifies loss of myofibrillar protein during protein undernutrition
Ishikawa, T., Kitaura, Y., Kadota, Y., Morishita, Y., Ota, M., Yamanaka, F., Xu, M., Ikawa, M., Inoue, N., Kawano, F., et al. (2017) · Scientific Reports · doi:10.1038/srep39825 · Cited by 26 · see citing works
Recharacterizing the Metabolic State of Energy Balance in Thrifty and Spendthrift Phenotypes
Hollstein, T., Basolo, A., Ando, T., Votruba, S. B., Walter, M. F., Krakoff, J. A., & Piaggi, P. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa098 · Cited by 25 · see citing works
Almendáriz-Palacios, C., Mousseau, D. D., Eskiw, C. H., & Gillespie, Z. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239220 · Cited by 28 · see citing works
Fibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior
Wu, C.-T., CHAFFIN, A. T. B., & Ryan, K. K. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030580 · Cited by 22 · see citing works
Tomé, D., Chaumontet, C., Even, P. C., Darcel, N., & Azzout-Marniche, D. (2019) · Physiology & Behavior · doi:10.1016/j.physbeh.2019.03.012 · Cited by 24 · see citing works
Methionine restriction alleviates diabetes-associated cognitive impairment via activation of FGF21
Zhang, Y., Wang, Y., Li, Y., Pang, J., Höhn, A., Dong, W., Gao, R. H., Liu, Y., Wang, D., She, Y., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103390 · Cited by 24 · see citing works
Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine
Fang, H., Stone, K. P., Forney, L. A., Wanders, D., & Gettys, T. W. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.773975 · Cited by 24 · see citing works
Self-citationRoux-en-Y gastric bypass surgery is effective in fibroblast growth factor-21 deficient mice
Morrison, C. D., Zheng, H., Mumphrey, M. B., Townsend, R. L., Münzberg, H., Ye, J., & Berthoud, H. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2016.08.005 · Cited by 23 · see citing works
Self-citationPak, H. H., Richardson, N. E., Green, C. L., Brinkman, J. A., Yu, D., Tomasiewicz, J. L., Yang, S. E., Boyle, C., Konon, E. N., Ong, I. M., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-37177-3 · Cited by 24 · see citing works
Fibroblast growth factor 21: A “rheostat” for metabolic regulation?
She, Q.-Y., Bao, J., Wang, H.-Z., Liang, H., Huang, W., Wu, J., Zhong, Y.-W., Ling, H., Li, A., & Qin, S.-L. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155166 · Cited by 22 · see citing works
Jonsson, W. O., Mirek, E. T., Wek, R. C., & Anthony, T. G. (2022) · The FASEB Journal · doi:10.1096/fj.202200204rr · Cited by 20 · see citing works
FGF21 prevents low-protein diet-induced renal inflammation in aged mice
Fang, H., Ghosh, S., Sims, L. C., Stone, K. P., Hill, C. M., Spires, D. R., Ilatovskaya, D. V., Morrison, C. D., Gettys, T. W., & Stadler, K. (2021) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00107.2021 · Cited by 20 · see citing works
Self-citationÖrd, T., Örd, D., & Örd, T. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2018.01.014 · Cited by 20 · see citing works
- Authors
- Laeger, 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.
- Affiliations
- Pennington Biomedical Research Center (US)
- Corresponding author
- Morrison, Christopher D.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 16
- Issue
- 3
- Pages
- 707-716
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4956501
- OpenAlex
- W2465530714
- Cited by
- 206
- References
- 44
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 18 · 2023: 12 · 2022: 22 · 2021: 30 · 2020: 18 · 2019: 26 · 2018: 20 · 2017: 18 · 2016: 5
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by-nc-nd)
- Funders
- Nutrition Obesity Research Center, University of North Carolina (P30DK072476)
- Deutsche Forschungsgemeinschaft (ADA 1-12-BS-58, DK-096311, LA 3042/2-1, R01DK047348, R01DK092587)
- National Institutes of Health (R01DK081563, R01DK105032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- FGF21, GCN2, protein restriction, low-protein diet, amino acid sensing, dietary intake, energy expenditure, weight gain, metabolic gene expression, FGF21 knockout mice
- MeSH terms
- Animals, Body Weight, Dietary Proteins, Eating, Energy Metabolism, Fibroblast Growth Factors, Male, Mice, Inbred C57BL, Gene Expression, Protein Serine-Threonine Kinases, Mice, Knockout, Diet, Protein-Restricted, Mice
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