Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARα and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States
Open accessAbstract
Mice fed a high-fat, low-carbohydrate ketogenic diet (KD) exhibit marked changes in hepatic metabolism and energy homeostasis. Here, we identify liver-derived fibroblast growth factor 21 (FGF21) as an endocrine regulator of the ketotic state. Hepatic expression and circulating levels of FGF21 are induced by both KD and fasting, are rapidly suppressed by refeeding, and are in large part downstream of PPARalpha. Importantly, adenoviral knockdown of hepatic FGF21 in KD-fed mice causes fatty liver, lipemia, and reduced serum ketones, due at least in part to altered expression of key genes governing lipid and ketone metabolism. Hence, induction of FGF21 in liver is required for the normal activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD. These findings identify hepatic FGF21 as a critical regulator of lipid homeostasis and identify a physiological role for this hepatic hormone.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the liver, FGF21 upregulates β-oxidation.
“In the liver, FGF21 upregulates β-oxidation [160] and downregulates lipogenesis [167].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [160]
The Results report that knocking down FGF21 in ketogenic-diet-fed mice reduced the diet-induced expression of hepatic β-oxidation genes. The Discussion interprets this as reduced liver capacity to oxidize lipids. This supports a role for FGF21 in β-oxidation during ketosis, but the unqualified claim extends beyond the condition studied and implies a direct increase in oxidation rather than the reported changes in gene expression and inferred capacity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBAIBA and FGF21 increase hepatic β-oxidation.
“For instance, BAIBA [104] and FGF21 [160] have been shown to increase hepatic β-oxidation (6)”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [160]
The Results and Discussion (pages unavailable) show that FGF21 knockdown in ketogenic-diet-fed mice reduced expression of hepatic β-oxidation genes and likely reduced the liver’s capacity to oxidize lipids. This supports a role for FGF21 in hepatic β-oxidation during ketosis, but the paper does not directly show that increasing FGF21 increases measured β-oxidation generally. The separate BAIBA citation is not assessed here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFGF21 is expressed and released into the general circulation by several tissues such as the liver, white adipose tissue, brown adipose tissue, and the heart.
“The metabolic regulator FGF21 is expressed and released into the general circulation by several tissues such as the liver, WAT, BAT, and the heart.7, 8, 9, 10, 11”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [7]
Mice that overexpress FGF-21, a circulating FGF which is induced by a ketogenic diet, are lean and have increased brown fat, suggesting that the beneficial metabolic effects induced by a ketogenic diet are brought about in part by increases in BAT mass.
“Interestingly, mice that overexpress FGF-21, a circulating FGF which is induced by a ketogenic diet 106, are lean and have increased brown fat 107, suggesting that the beneficial metabolic effects induced by a ketogenic diet are brought about in part by increases in BAT mass.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [106]
FGF21 is transcriptionally induced during extended fasting through a PPARα-dependent mechanism and regulates the adaptive fasting response.
“FGF21 was initially proposed to be a late-fasting/starvation factor, because it is transcriptionally induced during extended fasting, through a mechanism dependent on the transcription factor PPARα, and it regulates the adaptive fasting response20,21.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [21]
FGF21 is classically recognized as a fasting hormone regulated by PPARα.
“Classically recognized as a fasting hormone regulated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) [150,151]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [150]
FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states.
“FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states (6, 7).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [7]
Knockdown of hepatic Fgf21 results in significantly elevated hepatic triglyceride and plasma lipid levels, and impaired ketosis.
“Knockdown of hepatic Fgf21 using adenovirus-mediated expression of short hairpin RNAs directed against Fgf21 mRNA resulted in significantly elevated hepatic triglyceride and plasma lipid levels, and impaired ketosis (7).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [7]
PPARα-mediated induction of FGF21 is important for the adaptive fasting response.
“Multiple groups discovered that PPARα-mediated induction of FGF21 is important for the adaptive fasting response (7, 54).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [7]
FGF21 was first identified as a hepatokine and is necessary for adaptation to fasting.
“Fibroblast growth factor 21 (FGF21) was first identified as an hepatokine 61 and has been shown to be necessary for the adaptation to fasting 62, 63.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [62]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
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
Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting
Kersten, S., Seydoux, J., Peters, J. M., Gonzalez, F. J., Desvergne, B., & Wahli, W. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6223 · Cited by 1,649 · 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
Reddy, J. K., & Hashimoto, T. (2001) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.21.1.193 · Cited by 955 · see citing works
Leone, T. C., Weinheimer, C. J., & Kelly, D. P. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.13.7473 · Cited by 943 · see citing works
Identification of a novel FGF, FGF-21, preferentially expressed in the liver
Nishimura, T., Nakatake, Y., Konishi, M., & Itoh, N. (2000) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00067-1 · Cited by 847 · see citing works
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 · see citing works
Aitman, T. J., Glazier, A. M., Wallace, C. A., Cooper, L. D., Norsworthy, P. J., Wahid, F. N., Al-Majali, K., Trembling, P. M., Mann, C. J., Shoulders, C. C., et al. (1999) · Nature Genetics · doi:10.1038/5013 · Cited by 728 · see citing works
LXRS AND FXR: The Yin and Yang of Cholesterol and Fat Metabolism
Kalaany, N. Y., & Mangelsdorf, D. J. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.68.033104.152158 · Cited by 619 · 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
Tomlinson, E., Fu, L., John, L., Hultgren, B., Huang, X., Renz, M., Stephan, J. P., Tsai, S. P., Powell-Braxton, L., French, D., et al. (2002) · Endocrinology · doi:10.1210/endo.143.5.8850 · Cited by 576 · see citing works
“New” hepatic fat activates PPARα to maintain glucose, lipid, and cholesterol homeostasis
Chakravarthy, M. V., Pan, Z., Zhu, Y., Tordjman, K. M., Schneider, J. G., Coleman, T., TURK, J. W., & Semenkovich, C. F. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.04.002 · Cited by 545 · see citing works
Fatty Acid Regulation of Hepatic Gene Transcription
Jump, D. Β., Botolin, D., Wang, Y., Xu, J., Christian, B., & Demeure, O. (2005) · Journal of Nutrition · doi:10.1093/jn/135.11.2503 · Cited by 477 · see citing works
Köster, A., Chao, Y. B., Mosior, M., Ford, A., Gonzalez-DeWhitt, P. A., Hale, J. E., Li, D., Qiu, Y., Fraser, C. C., Yang, D. D., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0476 · Cited by 427 · see citing works
Angptl3 regulates lipid metabolism in mice
Koishi, R., Ando, Y., Ono, M., Shimamura, M., Yasumo, H., Fujiwara, T., Horikoshi, H., & Furukawa, H. (2002) · Nature Genetics · doi:10.1038/ng814 · Cited by 420 · see citing works
A high-fat, ketogenic diet induces a unique metabolic state in mice
Kennedy, A. R., Pissios, P., Otu, H., Xue, B., Asakura, K., Furukawa, N., Marino, F. E., Liu, F.-F., Kahn, B. B., Libermann, T. A., et al. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00717.2006 · Cited by 420 · see citing works
Self-citationRodríguez, J. C., Gil‐Gómez, G., Hegardt, F. G., & Haro, D. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32234-2 · Cited by 378 · see citing works
Shimizugawa, T., Ono, M., Shimamura, M., Yoshida, K., Ando, Y., Koishi, R., Ueda, K., Inaba, T., Minekura, H., Kohama, T., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203215200 · Cited by 370 · see citing works
PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis
Li, A. C., & Glass, C. K. (2004) · Journal of Lipid Research · doi:10.1194/jlr.r400010-jlr200 · Cited by 357 · see citing works
A Ketogenic Diet Increases the Resistance to Pentylenetetrazole‐Induced Seizures in the Rat
Bough, K. J., & Eagles, D. A. (1999) · Epilepsia · doi:10.1111/j.1528-1157.1999.tb02066.x · Cited by 149 · see citing works
Petit, V., Arnould, L., Martin, P. G. P., Monnot, M.-C., Pineau, T., Besnard, P., & Niot, I. (2006) · Journal of Lipid Research · doi:10.1194/jlr.m600283-jlr200 · Cited by 147 · see citing works
Angiopoietin-like Protein 3 Mediates Hypertriglyceridemia Induced by the Liver X Receptor
Inaba, T., Matsuda, M., Shimamura, M., Takei, N., Terasaka, N., Ando, Y., Yasumo, H., Koishi, R., Makishima, M., & Shimomura, I. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213202200 · Cited by 138 · see citing works
Regulation of the angiopoietin-like protein 3 gene by LXR
Kaplan, R. A., Zhang, T., Hernandez, M., Gan, F. X., Wright, S. D., Waters, M. G., & Cai, T. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m200367-jlr200 · Cited by 127 · see citing works
Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes
Shimamura, M., Matsuda, M., Kobayashi, S., Ando, Y., Ono, M., Koishi, R., Furukawa, H., Makishima, M., & Shimomura, I. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)03058-9 · Cited by 112 · see citing works
Quant, P. A., Tubbs, P. K., & Brand, M. D. (1990) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1990.tb15291.x · Cited by 87 · see citing works
The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36
Febbraio, M., Guy, E. C., Coburn, C. T., et al. (2002) · Molecular and Cellular Biochemistry · doi:10.1023/a:1020515210972 · Cited by 87 · see citing works
Leptin Contributes to Slower Weight Gain in Juvenile Rodents on a Ketogenic Diet
Thio, L. L., Altay, E. E., Rensing, N. R., & Yamada, K. A. (2006) · Pediatric Research · doi:10.1203/01.pdr.0000238244.54610.27 · Cited by 85 · see citing works
Thumelin, S., Forestier, M., Girard, J. R., & Pégorier, J. P. (1993) · Biochemical Journal · doi:10.1042/bj2920493 · Cited by 80 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [22]22. Reddy, J.K. ∙ Hashimoto, T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system Annu. Rev. Nutr. 2001; 21:193-230 Crossref Scopus (794) PubMed Google Scholar
Cited by
Sorted by citations
Thyroid Hormone Regulation of Metabolism
Mullur, R., Liu, Y.-Y., & Brent, G. A. (2014) · Physiological Reviews · doi:10.1152/physrev.00030.2013 · Cited by 2,421 · see citing works
The Fibroblast Growth Factor signaling pathway
Ornitz, D. M., & Itoh, N. (2015) · WIREs Developmental Biology · doi:10.1002/wdev.176 · Cited by 2,050 · see citing works
The FGF family: biology, pathophysiology and therapy
Beenken, A., & Mohammadi, M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2792 · Cited by 1,945 · see citing works
Adipose-derived circulating miRNAs regulate gene expression in other tissues
Thomou, T., Mori, M. A., Dreyfuss, J. M., Konishi, M., Sakaguchi, M., Wolfrum, C., Rao, T. N., Winnay, J. N., Garcia-Martin, R., Grinspoon, S. K., et al. (2017) · Nature · doi:10.1038/nature21365 · Cited by 1,539 · 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
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
Homeostasis, Inflammation, and Disease Susceptibility
Kotas, M. E., & Medzhitov, R. (2015) · Cell · doi:10.1016/j.cell.2015.02.010 · Cited by 1,213 · see citing works
Xu, J., Lloyd, D. J., Hale, C., Stanislaus, S., Chen, M., Sivits, G., Vonderfecht, S., Hecht, R., Li, Y.-S., Lindberg, R. A., et al. (2009) · Diabetes · doi:10.2337/db08-0392 · Cited by 1,151 · see citing works
TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop
Settembre, C., De Cegli, R., Mansueto, G., Saha, P. K., Vetrini, F., Visvikis, O., Huynh, T., Carissimo, A., Palmer, D., Jürgen Klisch, T., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2718 · Cited by 1,022 · 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
Ketone bodies as signaling metabolites
Newman, J. C., & Verdin, E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.09.002 · Cited by 966 · see citing works
Bile acid signaling in metabolic disease and drug therapy
Li, T., & Chiang, J. Y. L. (2014) · Pharmacological Reviews · doi:10.1124/pr.113.008201 · Cited by 935 · see citing works
Understanding the Physiology of FGF21
Fisher, F. M., & Maratos-Flier, E. (2016) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105339 · Cited by 912 · see citing works
Self-citationThe secret life of NAD+: an old metabolite controlling new metabolic signaling pathways
Houtkooper, R. H., Cantó, C., Wanders, R. J., & Auwerx, J. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0026 · Cited by 899 · see citing works
Zhang, X., Yeung, D. C. Y., Karpisek, M., Stejskal, D., Zhou, Z.-G., Liu, F., Wong, R. L. C., Chow, W.-S., Tso, A. W. K., Lam, K. S. L., et al. (2008) · Diabetes · doi:10.2337/db07-1476 · Cited by 908 · see citing works
FGF/FGFR signaling in health and disease
Xie, Y., Su, N., Yang, J., Tan, Q., Huang, S., Jin, M., Ni, Z., Zhang, B., Zhang, D., Luo, F., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00222-7 · Cited by 904 · see citing works
β-Hydroxybutyrate: A Signaling Metabolite
Newman, J. C., & Verdin, E. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064916 · Cited by 872 · see citing works
“As described above, mTOR is also a checkpoint in the activation of ketogenesis; inhibition of mTORC1 is required to activate the transcription factors and hormones that control ketogenesis (4, 117).”
Adaptive thermogenesis in adipocytes: Is beige the new brown?
Wu, J., Cohen, P., & Spiegelman, B. M. (2013) · Genes & Development · doi:10.1101/gad.211649.112 · Cited by 828 · see citing works
Obesity 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-citationNonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases
Samuel, V. T., & Shulman, G. I. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.002 · Cited by 745 · see citing works
“FGF21 coordinates the metabolic shift from fed to fasted states; FGF21 regulates hepatic ketogenesis, gluconeogenesis, and adipose lipolysis (Badman et al., 2007; Inagaki et al., 2007).”
Kurosu, 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
Fon Tacer, K., Bookout, A. L., Ding, X., Kurosu, H., John, G. B., Wang, L., Goetz, R., Mohammadi, M., Kuro-o, M., Mangelsdorf, D. J., et al. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0142 · Cited by 700 · see citing works
Lin, Z., Tian, H., Lam, K. S. L., Lin, S., Hoo, R. C. L., Konishi, M., Itoh, N., Wang, Y., Bornstein, S. R., Xu, A., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.005 · Cited by 691 · see citing works
Thermogenic 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 · see citing works
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Geng, L., Lam, K. S. L., & Xu, A. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0386-0 · Cited by 607 · see citing works
Increased Fibroblast Growth Factor 21 in Obesity and Nonalcoholic Fatty Liver Disease
Dushay, J., Chui, P. C., Gopalakrishnan, G. S., Varela–Rey, M., Crawley, M., Fisher, F. M., Badman, M. K., Martinez–Chantar, M. L., & Maratos–Flier, E. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.04.054 · Cited by 607 · see citing works
Self-citationThe Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance
Watt, M. J., Miotto, P. M., De Nardo, W., & Montgomery, M. K. (2019) · Endocrine Reviews · doi:10.1210/er.2019-00034 · Cited by 615 · see citing works
Patti, M., Houten, S. M., Bianco, A. C., Bernier, R., Larsen, P. R., Holst, J. J., Badman, M. K., Maratos‐Flier, E., Mun, E. C., Pihlajamaki, J., et al. (2009) · Obesity · doi:10.1038/oby.2009.102 · Cited by 591 · 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 · see citing works
Cellular bioenergetics as a target for obesity therapy
Tseng, Y.-H., Cypess, A. M., & Kahn, C. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3138 · Cited by 591 · see citing works
New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond
Beuers, U., Trauner, M., Jansen, P., & Poupon, R. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.02.023 · Cited by 537 · see citing works
Dutchak, P. A., Katafuchi, T., Bookout, A. L., Choi, J. H., Yu, R. T., Mangelsdorf, D. J., & Kliewer, S. A. (2012) · Cell · doi:10.1016/j.cell.2011.11.062 · Cited by 537 · see citing works
GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans
Patel, S., Alvarez-Guaita, A., Melvin, A., Rimmington, D., Dattilo, A., Miedzybrodzka, E. L., Cimino, I., Maurin, A.-C., Roberts, G. P., Meek, C. L., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.12.016 · Cited by 509 · see citing works
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 · see citing works
Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice
Newman, J. C., Covarrubias, A. J., Zhao, M., Yu, X., Gut, P., Ng, C.-P., Huang, Y., Haldar, S., & Verdin, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.08.004 · Cited by 493 · see citing works
Dong, X. C., Copps, K. D., Guo, S., Li, Y., Kollipara, R., DePinho, R. A., & White, M. F. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.06.006 · Cited by 463 · 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
Suomalainen, A., Elo, J. M., Pietiläinen, K. H., Hakonen, A. H., Sevastianova, K., Korpela, M., Isohanni, P., Marjavaara, S. K., Tyni, T., Kiuru-Enari, S., et al. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70155-7 · Cited by 427 · see citing works
Wei, W., Dutchak, P. A., Wang, X., Ding, X., Wang, X., Bookout, A. L., Goetz, R., Mohammadi, M., Gerard, R. D., Dechow, P. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200797109 · Cited by 426 · see citing works
Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Degirolamo, C., Sabbà, C., & Moschetta, A. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.9 · Cited by 424 · see citing works
The New Biology and Pharmacology of Glucagon
Müller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D., & Tschöp, M. H. (2017) · Physiological Reviews · doi:10.1152/physrev.00025.2016 · Cited by 419 · see citing works
Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise
Schnyder, S., & Handschin, C. (2015) · Bone · doi:10.1016/j.bone.2015.02.008 · Cited by 419 · see citing works
FGF21 is an Akt‐regulated myokine
Izumiya, Y., Bina, H. A., Ouchi, N., Akasaki, Y., Kharitonenkov, A., & Walsh, K. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.10.021 · Cited by 415 · see citing works
Inhibition of Growth Hormone Signaling by the Fasting-Induced Hormone FGF21
Inagaki, T., Lin, V. Y., Goetz, R., Mohammadi, M., Mangelsdorf, D. J., & Kliewer, S. A. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.05.006 · Cited by 409 · see citing works
Benhamed, F., Denechaud, P.-D., Lemoine, M., Robichon, C., Moldes, M., Bertrand-Michel, J., Ratziu, V., Serfaty, L., Housset, C., Capeau, J., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci41636 · Cited by 408 · see citing works
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 · see citing works
Chavez, A. O., Molina-Carrion, M., Abdul-Ghani, M. A., Folli, F., DeFronzo, R. A., & Tripathy, D. (2009) · Diabetes Care · doi:10.2337/dc09-0684 · Cited by 390 · see citing works
Hondares, E., Rosell, M., Gonzalez, F. J., Giralt, M., Iglesias, R., & Villarroya, F. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.02.001 · Cited by 377 · see citing works
Brown fat as a therapy for obesity and diabetes
Cypess, A. M., & Kahn, C. R. (2010) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e328337a81f · Cited by 376 · see citing works
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 · see citing works
Self-citationHotta, Y., Nakamura, H., Konishi, M., Murata, Y., Takagi, H., Matsumura, S., Inoue, K., Fushiki, T., & Itoh, N. (2009) · Endocrinology · doi:10.1210/en.2009-0119 · Cited by 352 · 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
FGF21 Regulates Sweet and Alcohol Preference
Talukdar, S., Owen, B. M., Song, P., Hernandez, G., Zhang, Y., Zhou, Y., Scott, W. T., Paratala, B., Turner, T., Smith, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.008 · Cited by 342 · see citing works
Heinz, S., Freyberger, A., Lawrenz, B., Schladt, L., Schmuck, G., & Ellinger-Ziegelbauer, H. (2017) · Scientific Reports · doi:10.1038/srep45465 · Cited by 334 · see citing works
Regulation of Ketone Body Metabolism and the Role of PPARα
Grabacka, M., Pierzchalska, M., Dean, M., & Reiss, K. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17122093 · Cited by 305 · 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
Muise, E. S., Azzolina, B., Kuo, D. W., El-Sherbeini, M., Tan, Y., Yuan, X., Mu, J., Thompson, J. R., Berger, J. P., & Wong, K. K. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.044826 · Cited by 294 · see citing works
Mitochondrial myopathy induces a starvation-like response
Tyynismaa, H., Carroll, C. J., Raimundo, N., Ahola-Erkkilä, S., Wenz, T., Ruhanen, H., Guse, K., Hemminki, A., Peltola-Mjøsund, K. E., Tulkki, V., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq310 · Cited by 300 · see citing works
Liang, Q., Zhong, L., Zhang, J., Wang, Y., Bornstein, S. R., Triggle, C. R., Ding, H., Lam, K. S. L., & Xu, A. (2014) · Diabetes · doi:10.2337/db14-0541 · Cited by 299 · see citing works
Berglund, E. D., Li, C. Y., Bina, H. A., Lynes, S. E., Michael, M. D., Shanafelt, A. B., Kharitonenkov, A., & Wasserman, D. H. (2009) · Endocrinology · doi:10.1210/en.2009-0221 · Cited by 297 · see citing works
Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation
Crawford, P. A., Crowley, J. R., Sambandam, N., Muegge, B. D., Costello, E. K., Hamady, M., Knight, R., & Gordon, J. I. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902366106 · Cited by 278 · see citing works
Acute Exercise Induces FGF21 Expression in Mice and in Healthy Humans
Kim, K. H., Kim, S. H., Min, Y.-K., Yang, H.-M., Lee, J.-B., & Lee, M.-S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063517 · Cited by 290 · 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
Noble, E. E., Billington, C. J., Kotz, C. M., & Wang, C. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00776.2010 · Cited by 284 · see citing works
The fasting polypeptide FGF21 can enter brain from blood
Hsuchou, H., Pan, W., & Kastin, A. J. (2007) · Peptides · doi:10.1016/j.peptides.2007.10.007 · Cited by 280 · see citing works
Mraz, M., Bartlova, M., Lacinova, Z., Michalsky, D., Kasalicky, M., Haluzikova, D., Matoulek, M., Dostalova, I., Humenanska, V., & Haluzik, M. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03502.x · Cited by 279 · see citing works
Gonzalez-Gil, A. M., & Elizondo-Montemayor, L. (2020) · Nutrients · doi:10.3390/nu12061899 · Cited by 278 · see citing works
Fibroblast Growth Factor 21—Metabolic Role in Mice and Men
Staiger, H., Keuper, M., Berti, L., Hrabě de Angelis, M., & Häring, H.-U. (2017) · Endocrine Reviews · doi:10.1210/er.2017-00016 · Cited by 270 · see citing works
Forsström, S., Jackson, C. B., Carroll, C. J., Kuronen, M., Pirinen, E., Pradhan, S., Marmyleva, A., Auranen, M., Kleine, I.-M., Khan, N. A., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.019 · Cited by 252 · see citing works
The Glucagon Receptor Is Required for the Adaptive Metabolic Response to Fasting
Longuet, C., Sinclair, E. M., Maida, A., Baggio, L. L., Maziarz, M., Charron, M. J., & Drucker, D. J. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.09.008 · Cited by 272 · 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
Fisher, F. M., Chui, P. C., Nasser, I. A., Popov, Y., Cunniff, J. C., Lundasen, T., Kharitonenkov, A., Schuppan, D., Flier, J. S., & Maratos-Flier, E. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.07.044 · Cited by 263 · 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
Brown 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 · see citing works
Schlein, C., Talukdar, S., Heine, M., Fischer, A. W., Krott, L. M., Nilsson, S. K., Brenner, M. B., Heeren, J., & Scheja, L. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.006 · Cited by 252 · 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
Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions
Habegger, K. M., Stemmer, K., Cheng, C., Müller, T. D., Heppner, K. M., Ottaway, N., Holland, J., Hembree, J. L., Smiley, D., Gelfanov, V., et al. (2013) · Diabetes · doi:10.2337/db12-1116 · Cited by 245 · see citing works
Fibroblast growth factor 21 controls mitophagy and muscle mass
Oost, L. J., Kustermann, M., Armani, A., Blaauw, B., & Romanello, V. (2019) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12409 · Cited by 231 · see citing works
FGF21 attenuates lipolysis in human adipocytes – A possible link to improved insulin sensitivity
Arner, P., Pettersson, A., Mitchell, P. J., Dunbar, J. D., Kharitonenkov, A., & Rydén, M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.04.038 · Cited by 234 · see citing works
Fructose ingestion acutely stimulates circulating FGF21 levels in humans
Dushay, J. R., Toschi, E., Mitten, E. K., Fisher, F. M., Herman, M. A., & Maratos-Flier, E. (2015) · Molecular Metabolism · doi:10.1016/j.molmet.2014.09.008 · Cited by 233 · see citing works
Self-citationIrisin is inversely associated with intrahepatic triglyceride contents in obese adults
Zhang, H.-J., Zhang, X.-F., Ma, Z.-M., Pan, L.-L., Chen, Z., Han, H.-W., Han, C.-K., Zhuang, X.-J., Lu, Y., Li, X.-J., et al. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2013.04.030 · Cited by 234 · see citing works
Tanaka, T., Ngwa, J. S., van Rooij, F. J., Zillikens, M. C., Wojczynski, M. K., Frazier-Wood, A. C., Houston, D. K., Kanoni, S., Lemaitre, R. N., Luan, J., et al. (2013) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.052183 · Cited by 226 · see citing works
Keipert, 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: 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 · 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
FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
Søberg, S., Sandholt, C. H., Jespersen, N. Z., Toft, U., Madsen, A. L., von Holstein-Rathlou, S., Grevengoed, T. J., Christensen, K. B., Bredie, W. L. P., Potthoff, M. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.009 · Cited by 216 · see citing works
Central 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
Self-citationDefining 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
FGF21 and the late adaptive response to starvation in humans
Fazeli, P. K., Lun, M., Kim, S. M., Bredella, M. A., Wright, S., Zhang, Y., Lee, H., Catana, C., Klibanski, A., Patwari, P., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci83349 · Cited by 214 · see citing works
Metabolic adaptation in obesity and type ii diabetes: myokines, adipokines and hepatokines
Oh, K.-J., Lee, D., Kim, W., Han, B., Lee, S., & Bae, K.-H. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms18010008 · Cited by 210 · see citing works
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. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.06.044 · Cited by 206 · see citing works
Fibroblast Growth Factor-21 Is Induced in Human Skeletal Muscles by Hyperinsulinemia
Hojman, P., Pedersen, M., Nielsen, A. R., Krogh-Madsen, R., Yfanti, C., Åkerstrom, T., Nielsen, S., & Pedersen, B. K. (2009) · Diabetes · doi:10.2337/db09-0713 · Cited by 198 · see citing works
Ye, D., Wang, Y., Li, H., Jia, W., Man, K., Lo, C. M., Wang, Y., Lam, K. S. L., & Xu, A. (2014) · Hepatology · doi:10.1002/hep.27060 · Cited by 184 · 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
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
Exercise increases serum fibroblast growth factor 21 (FGF21) levels
Cuevas-Ramos, D., Almeda-Valdés, P., Meza-Arana, C. E., Brito-Córdova, G., Gómez-Pérez, F. J., Mehta, R., Oseguera-Moguel, J., & Aguilar-Salinas, C. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0038022 · Cited by 178 · see citing works
Inter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178 · see citing works
Timper, K., del Río-Martín, A., Cremer, A. L., Bremser, S., Alber, J., Giavalisco, P., Varela, L., Heilinger, C., Nolte, H., Trifunovic, A., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.001 · Cited by 170 · see citing works
A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism
Fisher, F. M., Kim, M., Doridot, L., Cunniff, J. C., Parker, T. S., Levine, D. M., Hellerstein, M. K., Hudgins, L. C., Maratos-Flier, E., & Herman, M. A. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2016.11.008 · Cited by 166 · see citing works
Self-citation
- Authors
- Badman, M. K., Pissios, P., Kennedy, A. R., Koukos, G., Flier, J. S., & Maratos-Flier, E.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Flier, Jeffrey S.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2007-06
- Volume
- 5
- Issue
- 6
- Pages
- 426-437
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2131622156
- Cited by
- 1,495
- References
- 29
- Citations by year
- 2026: 40 · 2025: 65 · 2024: 67 · 2023: 81 · 2022: 93 · 2021: 97 · 2020: 83 · 2019: 100 · 2018: 106 · 2017: 105 · 2016: 112 · 2015: 93 · 2014: 92 · 2013: 81 · 2012: 79
- FWCI
- 19.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk069983-05)
- National Heart, Lung, and Blood Institute (HL48739, R01HL048739)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK056116, P30DK046200, R01-DK-069983, 5P30DK46200-14)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Keywords
- FGF21, PPARα, ketogenic diet, hepatic lipid metabolism, ketogenesis, hepatic lipid oxidation, triglyceride clearance, fasting, refeeding, hepatic steatosis, serum ketones, hepatic hormones, energy homeostasis
- MeSH terms
- Adenoviridae, Animals, Hypolipidemic Agents, Cells, Cultured, Fibroblast Growth Factors, Gene Expression Regulation, Ketosis, Liver, Male, Mice, Inbred C57BL, Fenofibrate, RNA, Messenger, Transfection, Immunoblotting, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Hepatocytes, PPAR alpha, Lipid Metabolism, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
