The DOI matches its Crossref record; 28 of the 45 references it cites were found in a registry or an index.
Circulating Fibroblast Growth Factor 21 Is Induced by Peroxisome Proliferator-Activated Receptor Agonists But Not Ketosis in Man
Abstract
CONTEXT: Murine fibroblast growth factor (FGF) 21 is a nutritionally regulated hormone secreted by the liver principally in response to peroxisome proliferator-activated receptor-alpha (PPAR alpha) activation, which plays a critical role in regulating metabolism during ketosis. FGF21 is also a PPAR gamma target gene in mouse adipose tissue. Little information is available on FGF21 functions in humans. OBJECTIVE: The aim of the study was to measure plasma FGF21 during fasting, ketogenic diet, and PPAR agonist treatment in humans. DESIGN AND SETTING: We conducted a prospective study involving three patient groups at two university hospitals. PATIENTS: Eight healthy male volunteers underwent a 48-h period of starvation followed by 24-h refeeding (group 1); seven obese individuals were allocated to a low-carbohydrate diet for 3 months (group 2); and three groups of healthy, overweight or obese male volunteers received treatment with a PPAR alpha (20 microg/d GW590735) (n=6), PPAR delta (10 mg/d GW501516) (n=6), or PPAR gamma agonist (rosiglitazone) (n=10) for 2 wk (group 3). MAIN OUTCOME MEASURES: Fasting plasma FGF21 and serum 3-hydroxybutyrate were measured. RESULTS: There was no significant variation in human plasma FGF21 during fasting and refeeding. A 3-month ketogenic diet was associated with a 42% decline in plasma FGF21 levels. Circulating FGF21 increased significantly in response to treatment with PPAR alpha (39%) and PPAR delta (32%), but not PPAR gamma agonists. CONCLUSION: FGF21 does not play a major role in regulating the fasting response or ketosis in man. However, plasma FGF21 is elevated in response to pharmacological activation of PPAR alpha and PPAR delta and may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds.
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In the citing paper
“ketogenic diets do not induce plasma FGF21 levels in humans26,30,34”
From Metabolic messengers: FGF21 (2021) · cites this paper as [34]
In the citing paper
“Importantly, it is unclear whether there is any translational relevance of FGF21 to the beneficial effects of ketogenic diets in humans because circulating FGF21 levels fail to increase in humans in response to a ketogenic diet (19, 42, 73).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [19]
In the citing paper
“The effect of fasting and ketogenic diets to increase FGF21 is not nearly as robust in humans as initially observed in mice”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [131]
Citations
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FGF-21 as a novel metabolic regulator
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Fibroblast Growth Factor 21 Corrects Obesity in Mice
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The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21
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Items 101–154 of 154
Leptin, Acting at Central Level, Increases FGF21 Expression in White Adipose Tissue via PPARβ/δ
Mazuecos, L., Pintado, C., Rubio, B., Guisantes-Batán, E., Andrés, A., & Gallardo, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094624 · Cited by 21
“Although FGF21 expression and effects, including its browning capacity, are closely associated with PPARα and PPARG activity [62,63], a study in humans with PPARs agonists revealed that treatment with the PPARβ/δ agonist (GW501516) increased the circulating levels of FGF21, providing evidence of a metabolic relationsh…”
BackgroundFoo, J., Aronis, K. N., Chamberland, J. P., Paruthi, J., Moon, H., & Mantzoros, C. S. (2012) · Diabetes Care · doi:10.2337/dc12-0497 · Cited by 21
“The discrepancy in relation to other studies could be secondary to the shorter duration of fasting (11,13), different assays used (10–13,), different genders studied (13), and design of these studies.”
BackgroundResultPPAR Modulation of Kinase-Linked Receptor Signaling in Physiology and Disease
Rotman, N., & Wahli, W. (2010) · Physiology · doi:10.1152/physiol.00018.2010 · Cited by 20
“This has been documented for both mice and humans (8, 30, 66).”
Current understanding and controversies on the clinical implications of fibroblast growth factor 21
Badakhshi, Y., & Jin, T. (2020) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2020.1864278 · Cited by 20
“Ketosis stimulated FGF21 expression is, however, not appreciably observed in human subjects [36].”
BackgroundMiehle, K., Ebert, T., Kralisch, S., Hoffmann, A., Kratzsch, J., Schlögl, H., Stümvoll, M., & Faßhauer, M. (2016) · Cytokine · doi:10.1016/j.cyto.2016.04.015 · Cited by 19
“These data are in accordance with recent studies indicating that peroxisome proliferator–activated receptor a activation by both FFAs [37,38] and fibrates [39] increases circulating FGF21 levels.”
ResultEmerging targets and potential therapeutic agents in non-alcoholic fatty liver disease treatment
Yang, Y., Zhao, Y., Li, W., Wu, Y., Wang, X., Wang, Y., Liu, T.-M., Ye, T., Xie, Y., Cheng, Z., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112311 · Cited by 17
Protein-Restricted Diets and Their Impact on Metabolic Health and Aging
Kim, S. Q., Spann, R. A., Hill, C. M., Berryman, C. E., Berthoud, H., McDougal, D. H., He, Y., Münzberg, H., Yu, S., & Morrison, C. D. (2025) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-121624-114918 · Cited by 17
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Predictors of weight loss in patients with obesity treated with a Very Low-Calorie Ketogenic Diet
Ernesti, I., Baratta, F., Watanabe, M., Risi, R., Camajani, E., Persichetti, A., Tuccinardi, D., Mariani, S., Lubrano, C., Genco, A., et al. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1058364 · Cited by 19
“Mice fed a ketogenic diet express increased FGF21 levels (24, 25), whereas our group and others have demonstrated that ketogenic diets result in decreased FGF21 levels in human subjects (26, 27).”
BackgroundFGF21 mediating the Sex-dependent Response to Dietary Macronutrients
Sauza, K. A. S., & Ryan, K. K. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae363 · Cited by 14
Effects of Weight Loss on FGF-21 in Human Subjects: An Exploratory Study
Headland, M. L., Clifton, P. M., & Keogh, J. B. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16234877 · Cited by 13
Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice
Albarazanji, K. A., Jennis, M., Cavanaugh, C., Lang, W., Singh, B., Lanter, J. C., Lenhard, J. M., & Hornby, P. J. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00404.2018 · Cited by 13
Kim, S. Q., Spann, R. A., Khan, M. S. H., Berthoud, H., Münzberg, H., Albaugh, V. L., He, Y., McDougal, D. H., Soto, P. L., Yu, S., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2024.110010 · Cited by 10
LPS infusion suppresses serum FGF21 levels in healthy adult volunteers
Lauritzen, E. S., Rittig, N. F., Bach, E., Møller, N., & Bjerre, M. (2017) · Endocrine Connections · doi:10.1530/ec-16-0103 · Cited by 12
KLOTHO, FGF21 AND FGF23: NOVEL PATHWAYS TO MUSCULOSKELETAL HEALTH?
Bartali, B., Semba, R. D., & de Araújo, A. B. (2013) · The Journal of Frailty & Aging · doi:10.14283/jfa.2013.26 · Cited by 12
“FGF21 expression in the liver is primarily induced by prolonged fasting through peroxisome proliferator-activated receptor (PPAR)-α activation and in white adipose tissue by feeding through activation of PPAR-y, a master transcriptional regulator of adipogenesis (31).”
BackgroundQian, Z., Zhang, Y., Yang, N., Nie, H., Yang, Z. L., Luo, P., Wei, X., Guan, Y., Huang, Y., Yan, J., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.984828 · Cited by 11
“003); while CR with <30E% protein (36– 40) or CR with unspecified protein content (32, 41, 42) did not significantly affected the cFGF21 level (Figure 5, p=0.”
BackgroundInfluentialResponse of Liver Metabolic Pathways to Ketogenic Diet and Exercise Are Not Additive
Huang, T.-Y., Goldsmith, F., Fuller, S. E., Simon, J., Batdorf, H. M., Scott, M. C., Essajee, N. M., BROWN, J. M., Burk, D. H., Morrison, C. D., et al. (2019) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002105 · Cited by 11
The Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review
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Research progress on the role of FGF21 in insulin resistance
Zhang, H., Zhu, R., Sun, Q., & Du, L. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1619462 · Cited by 10
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Sex Differences in Ketogenic Diet Response Reveal Gonadal Hormone Interaction With FGF21 in Mice
Zhang, Y., Cochran, J. D., Souvenir, R., Tai, W. C., Xia, R., Gladwin, B. S., Barton, N. B., Pereira, R. O., & Abel, E. D. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf131 · Cited by 8
“Interestingly, KD has not been shown to significantly raise FGF21 levels in humans, unlike other dietary conditions such as starvation, high sugar intake, or dietary protein restriction [11, 24, 25, 34, 35].”
Schiavo, L., Santella, B., Mingo, M., Rossetti, G., Orio, M., & Pilone, V. (2025) · Nutrients · doi:10.3390/nu17152409 · Cited by 7
“In addition, nutritional ketosis activates peroxisome proliferator-activated receptor alpha (PPAR-α ) and increases fibroblast growth factor 21 (FGF21) expression, both of which are central to hepatic lipid catabolism, mitochondrial biogenesis, and metabolic flexibility [31].”
Handzlik‐Orlik, G., Owczarek, A. J., Więcek, A., Mossakowska, M., Zdrojewski, T. R., Chudek, A., Olszanecka‐Glinianowicz, M., & Chudek, J. T. (2024) · Aging · doi:10.18632/aging.206114 · Cited by 7
“This specific stimulus increases the hepatic production of FGF21 via peroxisome proliferator-activated receptor alpha (PPARα) and does not affect it in other tissues or may even decrease its expression in the pancreas [17, 18].”
BackgroundKuckuck, S., van der Valk, E. S., Scheurink, A. J. W., Lengton, R., Mohseni, M., Visser, J. A., Iyer, A. M., van den Berg, S. A. A., & van Rossum, E. F. C. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1010858 · Cited by 8
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“An investigation showed that a ketogenic diet significantly reduced blood FGF21 levels while it reduced body weight in obese human subjects [28].”
BackgroundPalomer, X., Wang, J.-R., Tang, X., Wu, S., Rodríguez‐Calvo, R., Wahli, W., & Vázquez‐Carrera, M. (2026) · Cells · doi:10.3390/cells15050464 · Cited by 5
Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans
Lauritzen, E. S., Svart, M. V., Voss, T. S., Møller, N., & Bjerre, M. (2020) · Endocrine Research · doi:10.1080/07435800.2020.1831015 · Cited by 5
UPRmt-regulated mitokines: novel strategies for myocardial injury repair
Gao, W., Liu, J., Zhang, W., Liu, B., & Shen, L. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1652353 · Cited by 4
Al-Kuraishy, H. M., Al-Gareeb, A. I., Jabir, M. S., & Albukhaty, S. (2023) · The Egyptian Journal of Internal Medicine · doi:10.1186/s43162-023-00238-9 · Cited by 5
“Furthermore, hepatic FGF21 expression is induced by PPAR-α [19]; thus, PPAR-α agonists can enhance FGF21 expression [99].”
BackgroundTherapeutic potential of FGF21 in diabetes
Davis, D., Garg, C., & Lahiri, S. (2017) · Journal of Medicinal Plants Studies · Cited by 4
Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism
Yang, Z., Zarbl, H., & Guo, G. L. (2024) · Molecular Pharmacology · doi:10.1124/molpharm.123.000831 · Cited by 3
Fibroblast Growth Factor 21 is a Regulator of Energy Metabolism in the Liver and Adipose Tissue
Matikainen, N. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-407869-7.00039-8 · Cited by 3
Stevanović, D., Hebert, A. J., Desai, B. N., Singhal, G., Adams, A. C., Flier, J. S., & Maratos–Flier, E. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.27.921361 · Cited by 3
“In contrast, in similar diet studies in humans neither fasting nor consumption of KD alter FGF21 levels [17,18].”
ResultFibroblast Growth Factor 21 as a Regulator of Energy Metabolism in the Liver and Adipose Tissue
Matikainen, N., & Söderlund, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816093-0.00013-6 · Cited by 2
Jain, U., Srivastava, P., Sharma, A., Sinha, S., & Johari, S. (2024) · Current Diabetes Reviews · doi:10.2174/0115733998265915231116043813 · Cited by 3
Fibroblast growth factor 21: new insights from human studies
Hansen, J. S., & Plomgaard, P. (2016) · Cardiovascular Endocrinology · doi:10.1097/xce.0000000000000084 · Cited by 2
Plomgaard, P., & Weigert, C. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3193 · Cited by 2
Relationship Between Circulating FGF21 and Bone Mineral Density: An Exploratory StudyPreprint
Peterson, M. N., Czanstkowski, S., Richardson, K. A., & Funderburk, L. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.16.638516 · Cited by 2
“(7,10) Thus measurements of FGF21 concentrations on a particular day may not accurately reflect the average concentrations present in a person.”
Merrild, C., Johansen, V. B. I., Clemmensen, C., & Ranea‐Robles, P. (2026) · The Journal of Physiology · doi:10.1113/jp289817 · Cited by 1
Wali, J. A., Ramos-Nieves, J. M., Binia, A., & van der Beek, E. M. (2026) · Advances in Nutrition · doi:10.1016/j.advnut.2026.100713 · Cited by 1
“For example, a 3-mo KD regimen in participants with obesity resulted in 9% weight loss but paradoxically produced a 42% decline in FGF21 concentrations (compared with baseline) [98].”
Single and Multiple Doses of Seladelpar Decrease Diurnal Markers of Bile Acid Synthesis in Mice
Cable, E. E., Stebbins, J. W., Johnson, J. D., Choi, Y., Song, J., Gatto, S., Onorato, M. T., & McWherter, C. A. (2025) · PPAR Research · doi:10.1155/ppar/5423221 · Cited by 1
“Fgf21 had been reported to be upregulated in humans following the administration of PPAR α and PPAR δ agonists [36] as well as after seladelpar administration in mice [24].”
Schinner, S. (2010) · Yearbook of Endocrinology · doi:10.1016/s0084-3741(10)79495-6 · Cited by 1
Cetoacidosis diabética: Fisiopatología y alteraciones del medio interno
Rojas, F. R., Arias, A. C., Umaña, D. R., Loría, A. R., & Urhan, A. S. (2018) · Revista Médica de la Universidad de Costa Rica · doi:10.15517/rmucr.v12i1.34611
Means, A. R. (2012) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.13865958.15303059
A novel approach to growth hormone therapyPreprint
Боміхов, О. В. (2022) · OSF Preprints (OSF Preprints) · doi:10.31219/osf.io/qsnka
Aguilar-Salinas, C. A. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.734059638.793558319
Peterson, M. N., Adair, K. E., & Funderburk, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.26.630421
Hypothalamus-liver talks: whispers in the language of metabolism
Ferreira, V., Fernández-González, I., Vattathara, J. J., Rodríguez-Díaz, A., Fernández-Sanmartín, P., & Diéguez, C. (2026) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-026-10031-y
Inter-organ communication in physiology and pathophysiology : a role for the ChREBP-FGF21 axis?
Carbinatti, T. (2024) · theses.fr (ABES) · doi:10.70675/5d147ab4zad37z4f6bzac51z32a08efeaa51
Biological functions and emerging interplay of FGF21 and GDF15 in metabolic diseases and aging
Salmón‐Gómez, L., Keipert, S., Catalán, V., Rodrı́guez, A., Becerril, S., Frühbeck, G., & Gómez‐Ambrosi, J. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00627-w
“GDF15 induction is mainly mediated via PPARγ-dependent transcriptional activation [218], whereas FGF21 induction is downstream of PPARγ and PPARα [211, 219].”
Metadata
- Authors
- Christodoulides, C., Dyson, P., Sprecher, D., Tsintzas, K., & Karpe, F.
- Affiliations
- Churchill Hospital (GB)
- GlaxoSmithKline (United States) (US)
- University of Nottingham (GB)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2009-09-01
- Volume
- 94
- Issue
- 9
- Pages
- 3594-3601
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2140313261
- Cited by
- 153
- References
- 45
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 11 · 2020: 8 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 12 · 2015: 6 · 2014: 9 · 2013: 4 · 2012: 13
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Wellcome Trust
- 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) › Dietary Effects on Health
- Keywords
- FGF21, PPARα agonist, PPARδ agonist, PPARγ agonists, ketosis, ketogenic diet, fasting and refeeding, beta-hydroxybutyrate, GW501516, rosiglitazone, obesity, metabolic regulation
- MeSH terms
- Adult, Fibroblast Growth Factors, Humans, Ketosis, Male, Prospective Studies, Peroxisome Proliferator-Activated Receptors, Diet, Ketogenic
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