The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.
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.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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.
Citations
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
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
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
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
Reddy, J. K., & Hashimoto, T. (2001) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.21.1.193 · Cited by 991
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
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
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
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 733
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 623
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 584
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
“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 557
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
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
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
Self-citationAngptl3 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 379
Rodríguez, 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
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
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 339
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 150
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
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
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 111
Regulation of the angiopoietin-like protein 3 gene by LXR
Kaplan, R., Zhang, T., Hernandez, M., Gan, F. X., Wright, S. D., Waters, M. G., & Cai, T.-Q. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m200367-jlr200 · Cited by 106
The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36
Febbraio, M., Guy, E. C., Coburn, C. T., Knapp, F. F., Beets, A. L., Abumrad, N. A., & Silverstein, R. L. (2002) · Molecular and Cellular Biochemistry · doi:10.1023/a:1020515210972 · Cited by 89
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
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
Thumelin, S., Forestier, M., Girard, J. R., & Pégorier, J. P. (1993) · Biochemical Journal · doi:10.1042/bj2920493 · Cited by 80
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
The Fibroblast Growth Factor signaling pathway
Ornitz, D. M., & Itoh, N. (2015) · WIREs Developmental Biology · doi:10.1002/wdev.176 · Cited by 2,050
The FGF family: biology, pathophysiology and therapy
Beenken, A., & Mohammadi, M. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2792 · Cited by 1,945
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
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
Metadata
- 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 (medical) › 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
