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FGF21 Requires βklotho to Act In Vivo
Open accessAbstract
FGF21 has gradually become a focal point in metabolic research given its intriguing and complex biology and relevance to drug discovery. Despite the large amount of accumulated data, there remains a dearth of understanding of FGF21 physiology at the molecular/whole organism level. The scaffold protein βklotho (KLB) has previously been demonstrated in vitro to function as a co-factor permitting FGF21 mediated FGF receptor activation. However, the requirement for KLB in the propagation of FGF21 action in living animals has yet to be evaluated. To answer this question, we tested FGF21 in mice with total body ablation of KLB (KLBKO) and found no detectable activity. Firstly, we demonstrate that the disruption of KLB entirely abrogates acute FGF21 signaling in adipose tissue. We go on to show that this signaling defect translates to the absence of FGF21 mediated metabolic improvements in DIO mice. Indeed, KLBKO mice are totally refractory to FGF21-induced normalization of glucose homeostasis, attenuation of dyslipidemia, elevation of energy expenditure and weight loss. The lack of FGF21-driven effects was further substantiated at the transcriptional level with no FGF21 target gene signature detectable in adipose tissue and liver of KLBKO animals. Taken together our data show that KLB is a vital component of the FGF21 in vivo signaling machinery and is critically required for FGF21 action at the whole organism level.
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“loss of KLB abolishes all effects of FGF21 in vitro and in vivo46,53–56.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [55]
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“FGF21 functions in target tissues that express the traditional FGF receptor FGFR1c and the obligate coreceptor β-klotho (2, 27, 71, 99, 124, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [2]
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Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
FGF-21 as a novel metabolic regulator
Kharitonenkov, A., Shiyanova, T. L., Koester, A., Ford, A. M., Micanovic, R., Galbreath, E. J., Sandusky, G. E., Hammond, L. J., Moyers, J. S., Owens, R. A., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23606 · Cited by 2,125
Self-citationReceptor Specificity of the Fibroblast Growth Factor Family
Ornitz, D. M., Xu, J., Colvin, J. S., McEwen, D. G., MacArthur, C. A., Coulier, F., Gao, G., & Goldfarb, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.15292 · Cited by 1,871
Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.002 · Cited by 1,495
FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis
Fisher, F. M., Kleiner, S., Douris, N., Fox, E. C., Mepani, R. J., Verdeguer, F., Wu, J., Kharitonenkov, A., Flier, J. S., Maratos-Flier, E., et al. (2012) · Genes & Development · doi:10.1101/gad.177857.111 · Cited by 1,478 · cited 2×
“Of note, the metabolic effects of FGF21 in WT mice were largely reflected at the transcriptional level with significant induction of ‘‘browning’’ related genes in WAT such as UCP1 and PGC1a (Table 1), a phenomenon which has recently become synonymous with the mode of action of FGF21 in vivo [19,26,32,33].”
BackgroundSelf-citationReceptor Specificity of the Fibroblast Growth Factor Family
Zhang, X., Ibrahimi, O. A., Olsen, S. K., Umemori, H., Mohammadi, M., & Ornitz, D. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601252200 · Cited by 1,164
Fibroblast Growth Factor 21 Corrects Obesity in Mice
Coskun, T., Bina, H. A., Schneider, M. A., Dunbar, J. D., Hu, C. C., Chen, Y., Moller, D. E., & Kharitonenkov, A. (2008) · Endocrinology · doi:10.1210/en.2008-0816 · Cited by 1,031
Self-citationKurosu, H., Choi, M., Ogawa, Y., Dickson, A. S., Goetz, R., Eliseenkova, A. V., Mohammadi, M., Rosenblatt, K. P., Kliewer, S. A., & Kuro-o, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704165200 · Cited by 748
The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
Kharitonenkov, A., Wroblewski, V. J., Koester, A., Chen, Y.-F., Clutinger, C. K., Tigno, X. T., Hansen, B. C., Shanafelt, A. B., & Etgen, G. J. (2007) · Endocrinology · doi:10.1210/en.2006-1168 · Cited by 738
Self-citationThermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue
Hondares, E., Iglesias, R., Giralt, A., Gonzalez, F. J., Giralt, M., Mampel, T., & Villarroya, F. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.215889 · Cited by 623
βKlotho is required for metabolic activity of fibroblast growth factor 21
Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K. P., Goetz, R., Eliseenkova, A. V., Mohammadi, M., & Kuro-o, M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701600104 · Cited by 617
Gälman, C., Lundåsen, T., Kharitonenkov, A., Bina, H. A., Eriksson, M., Hafström, I., Dahlin, M., Åmark, P., Angelin, B., & Rudling, M. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.014 · Cited by 512
Self-citationWente, W., Efanov, A. M., Brenner, M. B., Kharitonenkov, A., Koster, A. M., Sandusky, G. E., Sewing, S., Treinies, I., Zitzer, H., & Gromada, J. (2006) · Diabetes · doi:10.2337/db05-1435 · Cited by 497
Self-citationHuman cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype
Pullinger, C. R., Eng, C. S., Salen, G., Shefer, S., BATTA, A. K., Erickson, S. K., Verhagen, A., Rivera, C. R., Mulvihill, S. J., Malloy, M. J., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15387 · Cited by 468
Human cholesterol 7α-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype
Pullinger, C. R., Eng, C. S., Salen, G., Shefer, S., BATTA, A. K., Erickson, S. K., Verhagen, A., Rivera, C. R., Mulvihill, S. J., Malloy, M. J., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215387 · Cited by 456
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
βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism
Ding, X., Boney-Montoya, J., Owen, B. M., Bookout, A. L., Coate, K. C., Mangelsdorf, D. J., & Kliewer, S. A. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.002 · Cited by 403
Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis
Badman, M. K., Koester, A., Flier, J. S., Kharitonenkov, A., & Maratos-Flier, E. (2009) · Endocrinology · doi:10.1210/en.2009-0532 · Cited by 362
Self-citationSuzuki, M., Uehara, Y., Motomura-Matsuzaka, K., Oki, J., Koyama, Y., Kimura, M., Asada, M., Komi-Kuramochi, A., Oka, S., & Toru, T. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0313 · Cited by 345
FGF‐21/FGF‐21 receptor interaction and activation is determined by βKlotho
Kharitonenkov, A., Dunbar, J. D., Bina, H. A., Bright, S. W., Moyers, J. S., Zhang, C., Ding, L., Micanovic, R., Mehrbod, S. F., Knierman, M. D., et al. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21357 · Cited by 333
Self-citationThe 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
Self-citationBrown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21
Chartoumpekis, D. V., Habeos, I. G., Ziros, P. G., Psyrogiannis, A. I., Kyriazopoulou, V. E., & Papavassiliou, A. G. (2011) · Molecular Medicine · doi:10.2119/molmed.2011.00075 · Cited by 252
Itoh, N. (2010) · Cell and Tissue Research · doi:10.1007/s00441-010-1024-2 · Cited by 241
Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo
Fisher, F. M., Estall, J. L., Adams, A. C., Antonellis, P. J., Bina, H. A., Flier, J. S., Kharitonenkov, A., Spiegelman, B. M., & Maratos–Flier, E. (2011) · Endocrinology · doi:10.1210/en.2011-0281 · Cited by 231
Self-citationFibroblast growth factor 21: from pharmacology to physiology
Kliewer, S. A., & Mangelsdorf, D. J. (2010) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2009.28449b · Cited by 219
Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance
Hale, C., Chen, M. M., Stanislaus, S., Chinookoswong, N., Hager, T., Wang, M., Véniant, M. M., & Xu, J. (2012) · Endocrinology · doi:10.1210/en.2010-1262 · Cited by 185
Differential Specificity of Endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in Complex with KLB
Yang, C., Jin, C., Li, X., Wang, F., McKeehan, W. L., & Luo, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033870 · Cited by 173
Müller, T. D., Sullivan, L. M., Habegger, K., Yi, C., Kabra, D., Grant, E., Ottaway, N., Krishna, R., Holland, J., Hembree, J., et al. (2012) · Journal of Peptide Science · doi:10.1002/psc.2408 · Cited by 156
FGF21 N‐ and C‐termini play different roles in receptor interaction and activation
Yie, J., Hecht, R., Patel, J., Stevens, J., Wang, W., Hawkins, N., Steavenson, S., Smith, S., Winters, D., Fisher, S., et al. (2009) · FEBS Letters · doi:10.1016/j.febslet.2008.11.023 · Cited by 149
FGF21 reloaded: challenges of a rapidly growing field
Kharitonenkov, A., & Larsen, P. J. (2010) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2010.11.003 · Cited by 147
Self-citationDifferent roles of N‐ and C‐ termini in the functional activity of FGF21
Micanovic, R., Raches, D. W., Dunbar, J. D., Driver, D. A., Bina, H. A., Dickinson, C. D., & Kharitonenkov, A. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21675 · Cited by 146
Self-citationRelevant use of Klotho in FGF19 subfamily signaling system in vivo
Tomiyama, K.-I., Maeda, R., Urakawa, I., Yamazaki, Y., Tanaka, T., Ito, S., Nabeshima, Y., Tomita, T., Odori, S., Hosoda, K., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913986107 · Cited by 144
FGF21 Promotes Metabolic Homeostasis via White Adipose and Leptin in Mice
Véniant, M. M., Hale, C., Helmering, J., Chen, M. M., Stanislaus, S., Busby, J., Vonderfecht, S., Xu, J., & Lloyd, D. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040164 · Cited by 141
Kharitonenkov, A. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.07.001 · Cited by 133
Self-citationErickson, S. K., Lear, S. R., Deane, S., Dubrac, S., Huling, S. L., Nguyen, L., Bollineni, J. S., Shefer, S., Hyogo, H., Cohen, D. E., et al. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m200489-jlr200 · Cited by 113
Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo
Adams, A. C., Coskun, T., Irizarry Rovira, A. R., Schneider, M. A., Raches, D. W., Micanovic, R., Bina, H. A., Dunbar, J. D., & Kharitonenkov, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038438 · Cited by 109
Self-citationCircadian expression of FGF21 is induced by PPARα activation in the mouse liver
Oishi, K., Uchida, D., & Ishida, N. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.09.046 · Cited by 95
Research works printed but not linked: 2
- Holland WL, Adams AC, Bauer S, Brozinick J, Kharitonenkov A, <etal>et al</etal>. (2012) Adiponectin is Critical for Acute Insulin Sensitizing Effects of FGF-21. International Symposium on Adiponectin Biology and Medicine. Tomakomai, Japan: Nature Publishing Group.
- AC Adams, 2012, Fundamentals of FGF19 & FGF21 action in vitro and in vivo, PLoS One, 7, e38438, 10.1371/journal.pone.0038438 · DOI · Paper page
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Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885
Self-citationThe therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
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Metadata
- Authors
- Adams, A. C., Cheng, C. C., Coskun, T., & Kharitonenkov, A.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Kharitonenkov, Alexei
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-11-27
- Volume
- 7
- Issue
- 11
- Pages
- e49977
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3507945
- OpenAlex
- W2086624706
- Cited by
- 181
- References
- 38
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 12 · 2020: 12 · 2019: 21 · 2018: 14 · 2017: 14 · 2016: 18 · 2015: 18 · 2014: 7 · 2013: 12
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- FGF21, β-Klotho, KLB, FGF receptor signaling, adipose tissue, glucose homeostasis, dyslipidemia, energy expenditure, weight loss, diet-induced obesity, metabolic signaling
- MeSH terms
- Klotho Proteins, Animals, Energy Metabolism, Female, Fibroblast Growth Factors, Gene Expression Regulation, Liver, Male, Membrane Proteins, Mice, Knockout, Mice, Adipose Tissue, White
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