Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo
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Fibroblast growth factors 19 (FGF19) and 21 (FGF21) have emerged as key regulators of energy metabolism. Several studies have been conducted to understand the mechanism of FGF19 and FGF21 action, however, the data presented has often been inconsistent and at times contradictory. Here in a single study we compare the mechanisms mediating FGF19/FGF21 actions, and how similarities/differences in actions at the cellular level between these two factors translate to common/divergent physiological outputs. Firstly, we show that in cell culture FGF19/FGF21 are very similar, however, key differences are still observed differentiating the two. In vitro we found that both FGF's activate FGFRs in the context of βKlotho (KLB) expression. Furthermore, both factors alter ERK phosphorylation and glucose uptake with comparable potency. Combination treatment of cells with both factors did not have additive effects and treatment with a competitive inhibitor, the FGF21 delta N17 mutant, also blocked FGF19's effects, suggestive of a shared receptor activation mechanism. The key differences between FGF21/FGF19 were noted at the receptor interaction level, specifically the unique ability of FGF19 to bind/signal directly via FGFR4. To determine if differential effects on energy homeostasis and hepatic mitogenicity exist we treated DIO and ob/ob mice with FGF19/FGF21. We find comparable efficacy of the two proteins to correct body weight and serum glucose in both DIO and ob/ob mice. Nevertheless, FGF21 and FGF19 had distinctly different effects on proliferation in the liver. Interestingly, in vivo blockade of FGF21 signaling in mice using ΔN17 caused profound changes in glycemia indicative of the critical role KLB and FGF21 play in the regulation of glucose homeostasis. Overall, our data demonstrate that while subtle differences exist in vitro the metabolic effects in vivo of FGF19/FGF21 are indistinguishable, supporting a shared mechanism of action for these two hormones in the regulation of energy balance.
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Disrupting leptin signaling using ob/ob or db/db mice abrogates the beneficial effects of FGF21 in lowering body weight in response to extended FGF21 administration.
“In addition, disrupting leptin signaling using ob/ob or db/db mice abrogates the beneficial effects of FGF21 in lowering body weight in response to extended FGF21 administration (3, 45, 51, 67, 139).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [3]
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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 · see citing works
Self-citationKlotho converts canonical FGF receptor into a specific receptor for FGF23
Urakawa, I., Yamazaki, Y., Shimada, T., Iijima, K., Hasegawa, H., Okawa, K., Fujita, T., Fukumoto, S., & Yamashita, T. (2006) · Nature · doi:10.1038/nature05315 · Cited by 1,846 · see citing works
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
Regulation of Fibroblast Growth Factor-23 Signaling by Klotho*
Kurosu, H., Ogawa, Y., Miyoshi, M., Yamamoto, M., Nandi, A., Rosenblatt, K., Baum, M., Schiavi, S., Hu, M.-C., Moe, O., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.c500457200 · Cited by 1,356 · see citing works
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 · see citing works
Self-citationObesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State
Fisher, F. M., Chui, P. C., Antonellis, P. J., Bina, H. A., Kharitonenkov, A., Flier, J. S., & Maratos-Flier, E. (2010) · Diabetes · doi:10.2337/db10-0193 · Cited by 830 · see citing works
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 · 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
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 · see citing works
Fu, L., John, L. M., Adams, S. H., Yu, X. X., Tomlinson, E., Renz, M. E., Williams, P. M., Soriano, R. H., Corpuz, R. T., Moffat, B., et al. (2004) · Endocrinology · doi:10.1210/en.2003-1671 · Cited by 580 · see citing works
A Mouse Model of Hepatocellular Carcinoma
Nicholes, K., Guillet, S., Tomlinson, E., Hillan, K., Wright, B., Frantz, G. D., Pham, T. A., Dillard-Telm, L., Tsai, S. P., Stephan, J.-P., et al. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)61177-7 · Cited by 359 · see citing works
Best Practices Guideline: Toxicologic Histopathology
Crissman, J. W., Goodman, D. G., Hildebrandt, P. K., Maronpot, R. R., Prater, D. A., Riley, J. H., Seaman, W. J., & Thake, D. C. (2004) · Toxicologic Pathology · doi:10.1080/01926230490268756 · Cited by 349 · see citing works
Suzuki, 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 · see citing works
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 329 · see citing works
Self-citationItoh, N. (2010) · Cell and Tissue Research · doi:10.1007/s00441-010-1024-2 · Cited by 247 · see citing works
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 229 · see citing works
Self-citationBadman, M. K., Kennedy, A. R., Adams, A. C., Pissios, P., & Maratos–Flier, E. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00357.2009 · Cited by 217 · see citing works
Self-citationThe Klotho gene family as a regulator of endocrine fibroblast growth factors.
Kurosu, H., & Kuro-o, M. (2009) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.10.052 · Cited by 196 · see citing works
Molecular determinants of FGF‐21 activity—synergy and cross‐talk with PPARγ signaling
Moyers, J. S., Shiyanova, T. L., Mehrbod, F., Dunbar, J. D., Noblitt, T. W., Otto, K. A., Reifel-Miller, A. E., & Kharitonenkov, A. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20847 · Cited by 193 · see citing works
Self-citationFGF19-induced Hepatocyte Proliferation Is Mediated through FGFR4 Activation
Wu, X., Ge, H., Lemon, B., Vonderfecht, S., Weiszmann, J., Hecht, R., Gupte, J., Hager, T., Wang, Z.-L., Lindberg, R., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.068783 · Cited by 186 · see citing works
Wu, A.-L., Coulter, S., Liddle, C., Wong, A., Eastham‐Anderson, J., French, D. M., Peterson, A. S., & Sonoda, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017868 · Cited by 185 · see citing works
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 · see citing works
Overview of the FGF23-Klotho axis
Kuro-o, M. (2010) · Pediatric Nephrology · doi:10.1007/s00467-009-1260-4 · Cited by 162 · see citing works
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 · see citing works
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 · see citing works
Self-citationFGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver
Huang, X., Yang, C., Luo, Y., Jin, C., Wang, F., & Mckeehan, W. (2007) · Diabetes · doi:10.2337/db07-0648 · Cited by 145 · see citing works
Relevant 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 143 · see citing works
Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling
Wu, X., Ge, H., Gupte, J., Weiszmann, J., Shimamoto, G., Stevens, J., Hawkins, N., Lemon, B., Shen, W., Xu, J., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c700130200 · Cited by 140 · see citing works
Kharitonenkov, A. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.07.001 · Cited by 133 · see citing works
Self-citationSeparating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19)
Wu, X., Ge, H., Lemon, B. D., Vonderfecht, S. L., Baribault, H., Weiszmann, J., Gupte, J., Gardner, J., Lindberg, R. A., Wang, Z., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009427107 · Cited by 104 · see citing works
Resistance to Chemotherapy Is Associated with Fibroblast Growth Factor Receptor 4 Up-Regulation
Roidl, A., Berger, H.-J., Kumar, S., Bange, J., Knyazev, P. G., & Ullrich, A. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0890 · Cited by 99 · see citing works
Fibroblast Growth Factor-21 as a Therapeutic Agent for Metabolic Diseases
Kharitonenkov, A., & Shanafelt, A. B. (2008) · BioDrugs · doi:10.2165/00063030-200822010-00004 · Cited by 98 · see citing works
Self-citationSelective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice
Wu, X., Ge, H., Lemon, B. D., Weiszmann, J., Gupte, J., Hawkins, N., Li, X., Tang, J., Lindberg, R. A., & Li, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907812106 · Cited by 88 · see citing works
C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors
Wu, X., Lemon, B. D., Li, X., Gupte, J., Weiszmann, J., Stevens, J. L., Hawkins, N., Shen, W. D., Lindberg, R. A., Chen, J., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803319200 · Cited by 86 · see citing works
Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands
Goetz, R., Ohnishi, M., Ding, X., Kurosu, H., Wang, L., Akiyoshi, J., Ma, J.-H., Gai, W.-M., Sidis, Y., Pitteloud, N., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06603-11 · Cited by 76 · see citing works
The Klotho gene family and the endocrine fibroblast growth factors
Kurosu, H., & Kuro‐o, M. (2008) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0b013e3282ffd994 · Cited by 65 · see citing works
Hormone-like fibroblast growth factors and metabolic regulation
Long, Y. C., & Kharitonenkov, A. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.04.002 · Cited by 55 · see citing works
Self-citationFibroblast growth factors as regulators of stem cell self-renewal and aging
Yeoh, J. S. G., & de Haan, G. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.11.005 · Cited by 46 · see citing works
Fibroblast Growth Factors, Fibroblast Growth Factor Receptors, Diseases, and Drugs
Chen, G., & Forough, R. (2006) · Recent Advances in Cardiovascular Drug Discovery (Formerly Recent Patents on Cardiovascular Drug Discovery) · doi:10.2174/157489006777442478 · Cited by 34 · see citing works
Naito (2010) · International Journal of Oncology · doi:10.3892/ijo_00000832 · Cited by 33 · see citing works
A Unique FGF23 with the Ability to Activate FGFR Signaling through Both αKlotho and βKlotho
Wu, X., Weiszmann, J., Ge, H., Baribault, H., Stevens, J. L., Hawkins, N., Vonderfecht, S. L., Gardner, J., Gupte, J., Sheng, J., et al. (2012) · Journal of Molecular Biology · doi:10.1016/j.jmb.2012.02.027 · Cited by 17 · see citing works
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The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
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 · see citing works
Self-citationAn FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice
Holland, W., Adams, A., Brozinick, J., Bui, H., Miyauchi, Y., Kusminski, C., Bauer, S., Wade, M., Singhal, E., Cheng, C. C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.03.019 · Cited by 525 · see citing works
Self-citationTalukdar, S., Zhou, Y., Li, D., Rossulek, M., Dong, J., Somayaji, V., Weng, Y., Clark, R., Lanba, A., Owen, B. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.02.001 · Cited by 496 · see citing works
Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies
Musso, G., Cassader, M., & Gambino, R. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.3 · Cited by 415 · see citing works
FGF21 Regulates Metabolism Through Adipose-Dependent and -Independent Mechanisms
BonDurant, L. D., Ameka, M., Naber, M. C., Markan, K. R., Idiga, S. O., Acevedo, M. R., Walsh, S. A., Ornitz, D. M., & Potthoff, M. J. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.005 · Cited by 330 · see citing works
FGF21 gene therapy as treatment for obesity and insulin resistance
Jiménez, V., Jambrina, C., Casana, E., Sacristan, V., MUÑOZ, S. A., Darriba, S., Rodó, J., Mallol, C., García, M., León, X., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201708791 · Cited by 319 · see citing works
Li, Y., Wong, K., Giles, A. J., Jiang, J., Lee, J. W., Adams, A. C., Kharitonenkov, A., Yang, Q., Gao, B., Guarente, L., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.10.059 · Cited by 281 · see citing works
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 · see citing works
Self-citationKeipert, S., Ost, M., Johann, K., Imber, F., Jastroch, M., van Schothorst, E. M., Keijer, J., & Klaus, S. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00330.2013 · Cited by 221 · see citing works
Fibroblast 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
Circulating fibroblast growth factors as metabolic regulators--a critical appraisal.
Angelin, B., Larsson, T., & Rudling, M. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.11.001 · Cited by 210 · see citing works
Mechanisms of Increased In Vivo Insulin Sensitivity by Dietary Methionine Restriction in Mice
Stone, K. P., Wanders, D., Orgeron, M., Cortez, C. C., & Gettys, T. W. (2014) · Diabetes · doi:10.2337/db14-0464 · Cited by 201 · 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
Self-citationRyan, K. K., Kohli, R., Gutierrez-Aguilar, R., Gaitonde, S. G., Woods, S. C., & Seeley, R. J. (2013) · Endocrinology · doi:10.1210/en.2012-1891 · Cited by 185 · see citing works
FGF21 Requires βklotho to Act In Vivo
Adams, A. C., Cheng, C. C., Coskun, T., & Kharitonenkov, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049977 · Cited by 181 · see citing works
Self-citationGong, Q., Hu, Z., Zhang, F., Cui, A., Chen, X., Jiang, H., Gao, J., Chen, X., Han, Y., Liang, Q., et al. (2016) · Hepatology · doi:10.1002/hep.28523 · Cited by 172 · see citing works
LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys
Adams, A. C., Halstead, C. A., Hansen, B. C., Irizarry, A. R., Martin, J. A., Myers, S. R., Reynolds, V. L., Smith, H. W., Wroblewski, V. J., & Kharitonenkov, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065763 · Cited by 169 · see citing works
Self-citationRational Design of a Fibroblast Growth Factor 21-Based Clinical Candidate, LY2405319
Kharitonenkov, A., Beals, J. M., Micanovic, R., Strifler, B. A., Rathnachalam, R., Wroblewski, V. J., Li, S., Köester, A., Ford, A. M., Coşkun, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058575 · Cited by 168 · see citing works
Self-citationGómez‐Ambrosi, J., Gallego-Escuredo, J. M., Catalán, V., Rodrı́guez, A., Domingo, P., Moncada, R., Valentí, V., Salvador, J., Giralt, M., Villarroya, F., et al. (2016) · Clinical Nutrition · doi:10.1016/j.clnu.2016.04.027 · Cited by 168 · see citing works
Fibroblast Growth Factor Signaling in Metabolic Regulation
Nies, V. J. M., Sancar, G., Liu, W., van Zutphen, T., Struik, D., Yu, R. T., Atkins, A. R., Evans, R. M., Jonker, J. W., & Downes, M. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00193 · Cited by 135 · see citing works
Wanders, D., Forney, L. A., Stone, K. P., Burk, D. H., Pierse, A., & Gettys, T. W. (2017) · Diabetes · doi:10.2337/db16-1212 · Cited by 137 · see citing works
Serum FGF21 levels are associated with brown adipose tissue activity in humans
Hanssen, M. J. W., Broeders, E. P. M., Samms, R. J., Vosselman, M. J., van der Lans, A. A. J. J., Cheng, C., Adams, A. C., Lichtenbelt, W. D. V. M., & Schrauwen, P. (2015) · Scientific Reports · doi:10.1038/srep10275 · Cited by 131 · see citing works
Self-citationEmerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases
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Fibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives
Somm, E., & Jornayvaz, F. R. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00134 · Cited by 118 · see citing works
FGF21 Revolutions: Recent Advances Illuminating FGF21 Biology and Medicinal Properties
Kharitonenkov, A., & DiMarchi, R. D. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.09.007 · Cited by 114 · see citing works
Self-citationKohn, K. W., Zeeberg, B. M., Reinhold, W. C., & Pommier, Y. G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099269 · Cited by 109 · see citing works
Alisi, A., Ceccarelli, S., Panera, N., Prono, F., Petrini, S., Stefanis, C. D., Pezzullo, M., Tozzi, A. E., Villani, A., Bedogni, G., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067160 · Cited by 105 · see citing works
Fibroblast growth factor 21 night watch: advances and uncertainties in the field
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Self-citationHenriksson, E., & Andersen, B. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.601349 · Cited by 95 · see citing works
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Omar, B. A., Andersen, B., Hald, J., Raun, K., Nishimura, E., & Åhrén, B. (2013) · Diabetes · doi:10.2337/db13-0710 · Cited by 76 · see citing works
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Self-citationWang, D., Zhu, W., Jie-ming, L., An, C., & Wang, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081190 · Cited by 73 · see citing works
Human FGF-21 Is a Substrate of Fibroblast Activation Protein
Coppage, A. L., Heard, K. R., DiMare, M. T., Liu, Y., Wu, W., Lai, J. H.-S., & Bachovchin, W. W. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151269 · Cited by 71 · see citing works
Dai, H., Hu, W., Zhang, L., Jiang, F., Mao, X., Yang, G., & Li, L. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03588-w · Cited by 65 · see citing works
Weng, Y., Chabot, J., Bernardo, B. L., Yan, Q., Zhu, Y., Brenner, M. B., Vage, C., Logan, A., Calle, R. A., & Talukdar, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119104 · Cited by 67 · see citing works
Hultman, K., Scarlett, J. M., Baquero, A. F., Cornea, A. M., Zhang, Y., Salinas, C. B. G., Brown, J. M., Morton, G. J., Whalen, E. J., Grove, K. L., et al. (2019) · The Journal of Comparative Neurology · doi:10.1002/cne.24668 · Cited by 65 · see citing works
Metabolic role of fibroblast growth factor 21 in liver, adipose and nervous system tissues
Lin, X., Liu, Y. B., & Hu, H. (2017) · Biomedical Reports · doi:10.3892/br.2017.890 · Cited by 61 · 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
Targeting the FGF19–FGFR4 pathway for cholestatic, metabolic, and cancerous diseases
Li, X., Lu, W., Kharitonenkov, A., & Luo, Y. (2024) · Journal of Internal Medicine · doi:10.1111/joim.13767 · Cited by 60 · see citing works
Self-citationMorán-Costoya, A., Proenza, A. M., Gianotti, M., Lladó, I., & Valle, A. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0044 · Cited by 58 · see citing works
Thompson, W. C., Zhou, Y., Talukdar, S., & Musante, C. J. (2016) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-016-9481-1 · Cited by 49 · see citing works
The Origins, Evolution, and Future of Dietary Methionine Restriction
Fang, H., Stone, K. P., Wanders, D., Forney, L. A., & Gettys, T. W. (2022) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062320-111849 · Cited by 47 · 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
Yang, C., Wang, C., Ye, M., Jin, C., He, W., Wang, F., McKeehan, W. L., & Luo, Y. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-94 · Cited by 47 · see citing works
Lv, J., Liu, Y., Yan, Y., Sun, D., Fan, L., Guo, Y., Fernandez, C., Bazzano, L., He, J., Li, S., et al. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.122.028219 · Cited by 43 · see citing works
Forney, L. A., Fang, H., Sims, L. C., Stone, K. P., Vincik, L. Y., Vick, A. M., Gibson, A. N., Burk, D. H., & Gettys, T. W. (2020) · Obesity · doi:10.1002/oby.22919 · Cited by 43 · see citing works
Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity
Agrawal, A., Parlee, S. D., Pérez–Tilve, D., Li, P., Pan, J. H., Mroz, P. A., Hansen, A. M. K., Andersen, B., Finan, B., Kharitonenkov, A., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.05.003 · Cited by 42 · see citing works
Self-citationKuzina, E. S., Ung, P. M. U., Mohanty, J., Tomé, F., Choi, J., Pardon, E., Steyaert, J., Lax, I., Schlessinger, A., Schlessinger, J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1822055116 · Cited by 41 · see citing works
Claflin, K. E., Sullivan, A. I., Naber, M. C., Flippo, K. H., Morgan, D. A., Neff, T. J., Jensen-Cody, S. O., Zhu, Z., Zingman, L. V., Rahmouni, K., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101564 · Cited by 37 · see citing works
Lee, D. V., Li, D., Yan, Q., Zhu, Y., Goodwin, B. J., Calle, R. A., Brenner, M. B., & Talukdar, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0111767 · Cited by 38 · see citing works
Perturbations of Fibroblast Growth Factors 19 and 21 in Type 2 Diabetes
Roesch, S. L., Styer, A. M., Wood, G. C., Kosak, Z., Seiler, J. L., Benotti, P. N., Petrick, A. T., Gabrielsen, J. D., Strodel, W. E., Gerhard, G. S., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116928 · Cited by 36 · see citing works
Johnson, C. L., Mehmood, R., Laing, S. W., Stepniak, C. V., Kharitonenkov, A., & Pin, C. L. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00559.2013 · Cited by 36 · see citing works
Self-citationTargeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target
Liu, W., Xie, D.-M., Zhu, G., Huang, G., Lin, Y.-Q., Wang, L., Shi, K., Hu, B., Braddock, M., Chen, Y., et al. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.997711 · Cited by 36 · see citing works
The anti-obesity effect of FGF19 does not require UCP1-dependent thermogenesis
Antonellis, P. J., Droz, B. A., Cosgrove, R., O’Farrell, L. S., Coşkun, T., Perfield, J. W., Bauer, S. M., Wade, M. R., Chouinard, T. E., Brozinick, J. T., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.09.006 · Cited by 35 · see citing works
Self-citationGlucagon receptor signaling regulates weight loss via central KLB receptor complexes
Nason, S. R., Antipenko, J., Presedo, N., Cunningham, S. E., Pierre, T. H., Kim, T., Paul, J. R., Holleman, C., Young, M. E., Gamble, K. L., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.141323 · Cited by 34 · see citing works
Self-citationRamanjaneya, M., Bensila, M., Bettahi, I., Jerobin, J., Samra, T. A., Aye, M. M., Alkasem, M., Siveen, K. S., Sathyapalan, T., Skarulis, M. C., et al. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.568500 · Cited by 34 · see citing works
FGF21 increases water intake, urine output and blood pressure in rats
Turner, T., Chen, X., Zahner, M. R., Opsahl, A., DeMarco, G. J., Boucher, M., Goodwin, B. J., & Perreault, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0202182 · Cited by 33 · see citing works
Rosenstock, M., Tseng, L., Pierce, A. A., Offman, E., Chen, C.-Y., Charlton, R., Margalit, M., & Mansbach, H. (2023) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.123.001618 · Cited by 31 · see citing works
Linking Nonalcoholic Fatty Liver Disease and Brain Disease: Focusing on Bile Acid Signaling
Ren, Z., Li, C.-X., Ma, C., Chen, D., Chen, J., Xu, W., Chen, C.-A., Cheng, F., & Wang, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113045 · Cited by 32 · see citing works
Role of fibroblast growth factors in organ regeneration and repair
Agha, E. E., Kosanovic, D., SCHERMULY, R. T., & Bellusci, S. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.10.009 · Cited by 31 · see citing works
Circulating FGF19 and FGF21 surge in early infancy from infra- to supra-adult concentrations
Sánchez‐Infantes, D., Gallego-Escuredo, J. M., Díaz, M., Aragonès, G., Sebastiani, G., López‐Bermejo, A., de Zegher, F., Domingo, P., Villarroya, F., & Ibáñez, L. (2015) · International Journal of Obesity · doi:10.1038/ijo.2015.2 · Cited by 30 · see citing works
Zhang, N., Liu, C., Zhang, Y., Xu, D., Gui, L., Lu, Y., & Zhang, Q. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.02.065 · Cited by 30 · see citing works
Stone, K. P., Ghosh, S., Kovalik, J. P., Orgeron, M., Wanders, D., Sims, L. C., & Gettys, T. W. (2021) · Scientific Reports · doi:10.1038/s41598-021-83380-0 · Cited by 29 · see citing works
Interactions between FGF21 and BMP-2 in osteogenesis
Ishida, K., & Haudenschild, D. R. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.02.019 · Cited by 28 · 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
The cell adhesion molecule L1 regulates the expression of FGF21 and enhances neurite outgrowth
Huang, X., Hu, J., Li, Y., Yang, Z. Z., Zhu, H., Zhou, L., Ma, K., Schachner, M., Xiao, Z., & Li, Y. (2013) · Brain Research · doi:10.1016/j.brainres.2013.07.043 · Cited by 24 · see citing works
Emerging pharmacological treatment options for MAFLD
Rojas, Á., Lara, C., Múñoz‐Hernández, R., Gato, S., Ampuero, J., & Romero‐Gómez, M. (2022) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188221142452 · Cited by 24 · see citing works
Bariatric Surgery: Prevalence, Predictors, and Mechanisms of Diabetes Remission
Argyropoulos, G. A. (2015) · Current Diabetes Reports · doi:10.1007/s11892-015-0590-9 · Cited by 23 · see citing works
Fibroblast growth factor 19-targeted therapies for the treatment of metabolic disease
Rysz, J., Gluba-Brzózka, A., Mikhailidis, D. P., & Banach, M. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.1006357 · Cited by 23 · see citing works
Autocrine FGF1 signaling promotes glucose uptake in adipocytes
Nies, V. J. M., Struik, D., Liu, S., Liu, W., Kruit, J. K., Downes, M., van Zutphen, T., Verkade, H. J., Evans, R. M., & Jonker, J. W. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2122382119 · Cited by 23 · see citing works
Ezzat, S., Zheng, L., Florez, J., Stefan, N., Mayr, T., Hliang, M., Jablonski, K., Harden, M. V., Stančáková, A., Laakso, M., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.002 · Cited by 24 · see citing works
RetractedHansen, A. M. K., Vienberg, S. G., Lykkegaard, K., Zhao, X., Tingqing, G., Han, D., Zhang, X., Thøgersen, H., Sass‐Ørum, K., Tagmose, T. M., et al. (2018) · Biochemical Journal · doi:10.1042/bcj20180555 · Cited by 23 · see citing works
Kanasaki, K. (2020) · Journal of Diabetes Investigation · doi:10.1111/jdi.13219 · Cited by 23 · see citing works
Wang, D., Xu, S., Ding, W., Zhu, C., Deng, S., Qiu, X., & Wang, Z. (2018) · Journal of Diabetes Investigation · doi:10.1111/jdi.12859 · Cited by 21 · see citing works
The role of FGF19 in metabolic regulation: insights from preclinical models to clinical trials
de Carvalho, M. B., Jorge, G. M. C. P., Zanardo, L. W., Hamada, L. M., Izabel, L. D. S., Santoro, S., & Magdalon, J. (2024) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00156.2024 · Cited by 21 · see citing works
Dzhemileva, L. U., Захарова, Е. Н., Goncharenko, A. O., Vorontsova, M. V., Roumiantsev, S. A., Mokrysheva, N. G., Loguinova, M. Y., & Chekhonin, V. P. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1497298 · Cited by 24 · see citing works
Guo, J., Chen, H.-H., Lee, W., Chen, S., Lee, S., & Chen, C. (2022) · Nutrients · doi:10.3390/nu14030645 · Cited by 20 · see citing works
Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway
Yu, D., Ye, X., Wu, Q., Li, S., Yang, Y., He, J., Liu, Y., Zhang, X., Yuan, Q., Liu, M., et al. (2015) · Endocrine · doi:10.1007/s12020-015-0801-9 · Cited by 19 · see citing works
Mirrazavi, Z. S., & Behrouz, V. (2024) · Clinical Nutrition · doi:10.1016/j.clnu.2024.01.005 · Cited by 20 · see citing works
Fibroblast Growth Factor 21-Null Mice Do Not Exhibit an Impaired Response to Fasting
Antonellis, P. J., Hayes, M. P., & Adams, A. C. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00077 · Cited by 17 · see citing works
Self-citationHu, X., Xiong, Q., Xu, Y., Zhang, X., Pan, X., Ma, X., Bao, Y., & Jia, W. (2017) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2017.10.009 · Cited by 17 · see citing works
Antonellis, P. J., Kharitonenkov, A., & Adams, A. C. (2014) · Journal of Animal Science · doi:10.2527/jas.2013-7076 · Cited by 16 · see citing works
Self-citationNovel Sandwich Immunoassays for The Measurement of Total and Active Fgf21
Umberger, T. S., Sloan, J. H., Chen, J., Cheng, C., Siegel, R. W., Qian, Y., Troutt, J. S., & Konrad, R. J. (2014) · Bioanalysis · doi:10.4155/bio.14.241 · Cited by 16 · see citing works
Wean, J. B., & Smith, B. N. (2021) · Endocrinology · doi:10.1210/endocr/bqab021 · Cited by 14 · see citing works
Gao, R., Kanasaki, K., Li, J., Kitada, M., Okazaki, T., & Koya, D. (2019) · FEBS Open Bio · doi:10.1002/2211-5463.12638 · Cited by 14 · see citing works
Stone, S., Wegner, D., Wambach, J., Cole, F. S., Urano, F., & Ornitz, D. M. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa138 · Cited by 12 · see citing works
PATEL, V. G., Joharapurkar, A. A., Kshirsagar, S. G., Patel, H., Pandey, D., Patel, D. N., Sutariya, B., Patel, M. S., Bahekar, R. H., & Jain, M. R. (2017) · Drug Research · doi:10.1055/s-0043-118808 · Cited by 11 · see citing works
Endocrine FGFs and their signaling in the brain: Relevance for energy homeostasis
Zangerolamo, L., Carvalho, M. U. W. B. D., Velloso, L. A., & Barbosa, H. C. L. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176248 · Cited by 11 · see citing works
Therapeutic Role of Fibroblast Growth Factor 21 (FGF21) in the Amelioration of Chronic Diseases
Opoku, Y. K., Liu, Z., Afrifa, J., Khoso, M. H., Ren, G., & Li, D. (2019) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-019-09820-8 · Cited by 10 · see citing works
Fibroblast Growth Factor 19 in Gestational Diabetes Mellitus and Fetal Growth
Yang, M., Huang, R., Liu, X., Xu, Y., Wang, W., He, H., Zhang, G., Zheng, T., Fang, F., Fan, J., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.805722 · Cited by 10 · see citing works
Styer, A. M., Roesch, S. L., & Argyropoulos, G. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085558 · Cited by 9 · see citing works
Effect of polyhexamethylene biguanide on rat liver
Chowdhury, A., Arnold, L. L., Wang, Z., Pennington, K. L., Dodmane, P. R., Farragut-Cardoso, A. P., Klaunig, J. E., Cros, D., Creppy, E. E., & Cohen, S. M. (2018) · Toxicology Letters · doi:10.1016/j.toxlet.2017.12.032 · Cited by 9 · see citing works
The Diagnostic Role of FGF 21 in Endometrial Cancer and Other Pathologies of the Uterine Corpus
Jagodzińska, A., Chudecka-Glaz, A. M., Michalczyk, K., Pius‐Sadowska, E., Wieder-Huszla, S., Jurczak, A., & Machaliński, B. (2023) · Diagnostics · doi:10.3390/diagnostics13030399 · Cited by 9 · see citing works
Zangerolamo, L., Carvalho, M. U. W. B. D., Solon, C., Sidarta-Oliveira, D., Soares, G. M., Marmentini, C., Boschero, A. C., Tseng, Y., Velloso, L. A., & Barbosa, H. C. L. (2025) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00488.2024 · Cited by 8 · see citing works
Defective FGFR1 Signaling Disrupts Glucose Regulation: Evidence From Humans With FGFR1 Mutations
Stamou, M. I., Chiu, C. J., Jadhav, S. V., Lopes, V. F., Salnikov, K. B., Plummer, L., Lippincott, M. F., Lee, H., Seminara, S. B., & Balasubramanian, R. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae118 · Cited by 7 · see citing works
Wean, J., & Smith, B. N. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.765359 · Cited by 5 · see citing works
Plasma Short-Chain Fatty Acids and Their Derivatives in Women with Gestational Diabetes Mellitus
Ivanovová, E., Piskláková, B., Friedecká, J., Krystyník, O., Friedecký, D., & Karásek, D. (2021) · Separations · doi:10.3390/separations8100188 · Cited by 5 · see citing works
Fibroblast Growth Factor–21 Ameliorates Rheumatoid Arthritis by Maintaining Articular Integrity
Opoku, Y. K., Liu, Z., Liu, H., Afrifa, J., Koranteng, H., Ren, G., & Li, D. (2019) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-019-09872-w · Cited by 4 · see citing works
- Authors
- 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.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Kharitonenkov, Alexei
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-05-31
- Volume
- 7
- Issue
- 5
- Pages
- e38438
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3365001
- OpenAlex
- W2050866090
- Cited by
- 109
- References
- 42
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 9 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 10 · 2013: 14 · 2012: 5
- FWCI
- 5.02
- 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)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- FGF19, FGF21, fibroblast growth factor, FGFR4, β-Klotho, energy metabolism, glucose homeostasis, ERK1/2 phosphorylation, glucose uptake, obesity, ob/ob mice, high-fat diet
- MeSH terms
- Klotho Proteins, Animals, Body Weight, Cell Line, Eating, Fibroblast Growth Factors, Glucuronidase, Male, Mice, Inbred C57BL, Signal Transduction, Receptors, Fibroblast Growth Factor, Hepatocytes, Cell Proliferation, Mice
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