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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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 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
Cites
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
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
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
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
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
Sorting out the roles of PPAR in energy metabolism and vascular homeostasis
Lefebvre, P. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27989 · Cited by 962
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
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
Cited by
Sorted by citations
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
PPARs in Obesity-Induced T2DM, Dyslipidaemia and NAFLD
Gross, B., Pawlak, M., Lefebvre, P., & Staels, B. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.135 · Cited by 778
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
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
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
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
Mardinoğlu, A., Wu, H., Björnson, E., Zhang, C., Hakkarainen, A., Räsänen, S., Lee, S., Mancina, R. M., Bergentall, M., Pietiläinen, K. H., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.005 · Cited by 465
“An earlier study also reported diet-induced reductions in FGF21 concentrations in humans upon increased protein intake (Christodoulides et al., 2009).”
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
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
Li, H., Fang, Q., Gao, F., Fan, J., Zhou, J., Wang, X., Zhang, H., Pan, X., Bao, Y., Xiang, K., et al. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.05.018 · Cited by 400
Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311
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
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
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
“Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element Binding Protein (ChREBP) stimulates hepatic FGF21 expression and that fructose may activate hepatic ChREBP more robustly than glucose.”
BackgroundMashili, F. L., Austin, R. L., Deshmukh, A. S., Fritz, T., Caidahl, K., Bergdahl, K., Zierath, J. R., Chibalin, A., Moller, D. E., Kharitonenkov, A., et al. (2011) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.1177 · Cited by 226
“In mice, but not humans, serum FGF21 levels are increased during ketogenesis [9,10], suggesting a species-specific physiological role for FGF21 in metabolic regulation.”
BackgroundResultFibroblast 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
“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).”
BackgroundEhrenborg, E., & Krook, A. (2009) · Pharmacological Reviews · doi:10.1124/pr.109.001560 · Cited by 222
“The positive influences on metabolic endpoints obtained in animal studies seem to hold up in the few human treatment studies published so far (Sprecher et al., 2007; Metabolex, 2008; Risérus et al., 2008; Christodoulides et al., 2009), the outcomes of which are summarized in Table 3.”
BackgroundFGF21 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
Jornayvaz, F. R., Jurczak, M. J., Lee, H., Birkenfeld, A. L., Frederick, D. W., Zhang, D., Zhang, X., Samuel, V. T., & Shulman, G. I. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00361.2010 · Cited by 213
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
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
“Furthermore, there is an extremely wide range of FGF21 concentrations observed in human serum [11,75] raising doubts as to the relevance of circulating FGF21 to its biological actions [74,76–78].”
BackgroundLi, H., Gao, Z., Zhang, J., Ye, X., Xu, A., Ye, J., & Jia, W. (2012) · Diabetes · doi:10.2337/db11-0846 · Cited by 193
“PPAR-a agonist is the major medicine in the induction of FGF21 (8,15).”
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
Jiang, S., Cheng, Y., Fang, Q., Shao, M., Zhang, Y., Liu, Y., Deng, Y., Shan, B., Liu, J., Li, H., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.565960 · Cited by 182
“In humans, however, FGF21 is merely modestly induced by PPAR agonists or fasting, and circulating levels of FGF21 are not increased during short term fasting or by ketogenic diets (27, 28).”
Yu, H., Xia, F., Lam, K. S., Wang, Y., Bao, Y., Zhang, J., Gu, Y., Zhou, P., Lu, J., Jia, W., et al. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.155184 · Cited by 170
Going Back to the Biology of FGF21: New Insights
Lewis, J. E., Ebling, F. J. P., Samms, R. J., & Tsintzas, K. (2019) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2019.05.007 · Cited by 170
Self-citationA 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
Ljubicic, V., Miura, P., Burt, M., Boudreault, L., Khogali, S. E. O., Lunde, J. A., Renaud, J.-M., & Jasmin, B. J. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr265 · Cited by 171
FGF21-based pharmacotherapy – potential utility for metabolic disorders
Gimeno, R. E., & Moller, D. E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2014.03.001 · Cited by 163
Liu, J., Xu, Y., Hu, Y., & Wang, G. (2014) · Metabolism · doi:10.1016/j.metabol.2014.11.009 · Cited by 139
“In addition to suppressing lipid synthesis by lowering the hepatic influx of fatty acids and reducing the expression of lipid synthesis genes, FGF21 also promotes fatty acid β-oxidation mediated by the peroxisome proliferator activated receptor α (PPARα)-FGF21 transcriptional regulatory axis [28,30,31].”
BackgroundFeingold, K. R., Grünfeld, C., Heuer, J. G., Gupta, A., Cramer, M. S., Zhang, T., Shigenaga, J. K., Patzek, S. M., Chan, Z. W., Moser, A. H., et al. (2012) · Endocrinology · doi:10.1210/en.2011-1496 · Cited by 130
A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response
Iroz, A., Montagner, A., Benhamed, F., Levavasseur, F., Polizzi, A., Anthony, E., Régnier, M., Fouché, E., Lukowicz, C., Cauzac, M., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.065 · Cited by 128
“Indeed, anti-diabetic therapies and PPARa agonists (fenofibrate or Wy-14653) significantly induce liverderived FGF21 in both mouse and human plasma (Christodoulides et al., 2009; Gälman et al., 2008; Lundåsen et al., 2007).”
Hoong, C. W. S., & Chua, M. W. J. (2021) · Endocrinology · doi:10.1210/endocr/bqab079 · Cited by 112
Samson, S. L., Sathyanarayana, P., Jogi, M., Gonzalez, E. V., Gutierrez, A., Krishnamurthy, R., Muthupillai, R., Chan, L., & Bajaj, M. (2011) · Diabetologia · doi:10.1007/s00125-011-2317-z · Cited by 110
“There was no effect on FGF21 levels following rosiglitazone (PPAR-γ agonist) treatment in non-diabetic participants [19].”
Regulation of FGF21 Expression and Secretion by Retinoic Acid Receptor-related Orphan Receptor α
Wang, Y., Solt, L. A., & Burris, T. P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.102160 · Cited by 106
PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders
Palomer, X., Barroso, E., Pizarro‐Delgado, J., Peña, L., Botteri, G., Zarei, M., Aguilar-Recarte, D., Montori-Grau, M., & Vázquez‐Carrera, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030913 · Cited by 110
“PPARβ/δ activation in hepatocytes blocks the effects of IL-6 by inhibiting the STAT3 pathway through several mechanisms and increasing FGF21 levels.”
BackgroundInfluentialGlucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet
ROSENBAUM, M. S., Hall, K. D., Guo, J., Ravussin, É., Mayer, L. S., Reitman, M. L., Smith, S. R., Walsh, B. T., & Leibel, R. L. (2019) · Obesity · doi:10.1002/oby.22468 · Cited by 105
“Cytokines, inflammatory markers, and other molecules The inflammatory cytokines (CRP and IL-6), adiponectin, PYY, the insulinogenic and lipoprotein lipase-activating GIP, and the insulinogenic GLP-1 and FGF21 were stable and significantly correlated between weeks 3 and 4 and within each diet (Table 5).”
BackgroundInfluentialFGF21 and the physiological regulation of macronutrient preference
Hill, C. M., Qualls-Creekmore, E., Berthoud, H.-R., Soto, P., Yu, S., McDougal, D. H., Münzberg, H., & Morrison, C. D. (2020) · Endocrinology · doi:10.1210/endocr/bqaa019 · Cited by 99
Emerging role of fibroblast growth factors 15/19 and 21 as metabolic integrators in the liver
Cicione, C., Degirolamo, C., & Moschetta, A. (2012) · Hepatology · doi:10.1002/hep.25929 · Cited by 95
Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis
Domouzoglou, E. M., & Maratos–Flier, E. (2011) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001941 · Cited by 93
Singhal, G., Kumar, G., Chan, S., Fisher, F. M., Ma, Y., Vardeh, H. G., Nasser, I. A., Flier, J. S., & Maratos-Flier, E. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.03.002 · Cited by 87
Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges
Martínez‐Garza, Ú., Torres‐Oteros, D., Yarritu, A., Marrero, P. F., Haro, D., & Relat, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194692 · Cited by 88
“However, unlike the murine model, in obese patients, a KD does not increase FGF21 serum levels [99] and even decreases its levels when a KD is combined with low calorie intake [100].”
BackgroundFibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus
So, W. Y., & Leung, P. S. (2016) · Medicinal Research Reviews · doi:10.1002/med.21390 · Cited by 85
“The engineered FGF21, FGF21(1-171)-WD22, is functionally indistinguishable from native FGF21 in terms of signaling activation, receptor binding specificity, and induction of adipose glucose uptake, but has increased potency with the more tolerant C-terminal modification.”
BackgroundMurata, Y., Konishi, M., & Itoh, N. (2011) · Journal of Nutrition and Metabolism · doi:10.1155/2011/981315 · Cited by 87
“In contrast, ketogenesis is independent of serum FGF21 levels [39, 40].”
BackgroundCirculating FGF21 Levels in Human Health and Metabolic Disease
Keuper, M., Häring, H., & Staiger, H. (2019) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0879-2968 · Cited by 83
“In subjects who were either healthy or had impaired glucose tolerance, no effects were reported for thiazolidinediones, which are potent PPARγ agonists clinically used as insulin sensitizers [39, 64, 96].”
BackgroundFibroblast growth factor 21 is not required for the antidiabetic actions of the thiazoladinediones
Adams, A. C., Coşkun, T., Cheng, C., O’Farrell, L. S., DuBois, S. L., & Kharitonenkov, A. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.05.005 · Cited by 75
Transcriptional control of physiological and pathological processes by the nuclear receptor PPARβ/δ
Tan, N. S., Vázquez‐Carrera, M., Montagner, A., Sng, M. K., Guillou, H., & Wahli, W. (2016) · Progress in Lipid Research · doi:10.1016/j.plipres.2016.09.001 · Cited by 75
Unraveling the Effects of PPARβ/δ on Insulin Resistance and Cardiovascular Disease
Vázquez‐Carrera, M. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.02.008 · Cited by 73
“In agreement with this, circulating FGF21 levels are increased in humans in response to pharmacological PPARβ/δ activation [49].”
BackgroundSpann, R. A., Morrison, C. D., & den Hartigh, L. J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.802541 · Cited by 76
Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology
Li, H., Zhang, J., & Jia, W. (2013) · Frontiers of Medicine · doi:10.1007/s11684-013-0244-8 · Cited by 67
“Circulating FGF21 levels are induced by fibrates and other PPARα agonists in humans [40,41].”
BackgroundHomeostatic sensing of dietary protein restriction: a case for FGF21
Hill, C. M., Berthoud, H.-R., Münzberg, H., & Morrison, C. D. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.06.002 · Cited by 68
Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice
Morovat, A., Weerasinghe, G. R., Nesbitt, V., Hofer, M., Agnew, T., Quaghebeur, G., Sergeant, K., Fratter, C., Guha, N., Mirzazadeh, M., et al. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6080080 · Cited by 68
“Unlike the mouse, in which hepatic FGF-21 is induced by peroxisomal proliferator-activated receptor-α (PPARα) and in response to fasting [9,10], the function of FGF-21 in humans is still not completely understood.”
BackgroundFactors mediating exercise‐induced organ crosstalk
Sabaratnam, R., Wojtaszewski, J. F. P., & Højlund, K. (2022) · Acta Physiologica · doi:10.1111/apha.13766 · Cited by 70
Kouno, T., Liu, X., Zhao, H., Kisseleva, T., Cable, E. E., & Schnabl, B. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102056 · Cited by 67
“In human subjects, plasma Fgf21 levels increase after the treatment with PPARD agonist GW590735 or PPARA agonist GW501516 (23).”
BackgroundMetabolic 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
“Similar to the findings in experiments with mice, PPARα stimulants (such as fibrates) increase the circulating level of FGF21 in the human body (66-68); however, the concentration of FGF21 is significantly increased in patients with rheumatoid arthritis after 7 days of fasting or in patients with obesity and diets low…”
ResultEffect of Nutrition on Statural Growth
Gat‐Yablonski, G., & Luca, F. D. (2017) · Hormone Research in Paediatrics · doi:10.1159/000456547 · Cited by 63
Tyynismaa, H., Raivio, T., Hakkarainen, A., Ortega‐Alonso, A., Lundbom, N. M. I., Kaprio, J. A., Rissanen, A., Suomalainen, A., & Pietiläinen, K. H. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-1326 · Cited by 61
Struik, D., Dommerholt, M. B., & Jonker, J. W. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000599 · Cited by 61
FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPARα and PPARγ Agonists
Li, X., Stanislaus, S., Asuncion, F., Niu, Q.-T., Chinookoswong, N., Villasenor, K., Wang, J., Wong, P., Boyce, R., Dwyer, D., et al. (2017) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2936 · Cited by 61
“Treatment with PPARg agonists increased FGF21mRNA expression in thewhite adipose tissues without changing its circulating levels.((13,15)) Hence, FGF21 was proposed to act locally to mediate PPARg-induced bone marrow adipogenesis, adipocyte insulin sensitization, body weight gain, and fluid retention.”
BackgroundInsights into the Role of PPARβ/δ in NAFLD
Chen, J., Montagner, A., Tan, N. S., & Wahli, W. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071893 · Cited by 61
“In rodents, both receptors play non-redundant roles in the liver to enhance ketogenesis through induction of Fgf21 and expression of fatty acid oxidation genes under fasting conditions [122,123].”
BackgroundHepatokines—A novel group of exercise factors
Weigert, C., Hoene, M., & Plomgaard, P. (2019) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-018-2216-y · Cited by 57
“In humans, 2 weeks’ treatment with PPARα and β, but not γ agonists, increases circulating FGF21 [46], which is in line with the fact that elevation of FFA—the endogenous agonist of PPAR α and β—for 4 h by infusion gives rise to an increase in plasma FGF21 [47].”
BackgroundLovrić, A., Granér, M., Björnson, E., Arif, M., Benfeitas, R., Nyman, K., Ståhlman, M., Pentikäinen, M. O., Lundbom, J., Hakkarainen, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-31865-w · Cited by 61
Physiological modulation of circulating FGF21: relevance of free fatty acids and insulin
Mai, K., Bobbert, T., Groth, C., Aßmann, A., Meinus, S., Kraatz, J., Andres, J., Arafat, A. M., Pfeiffer, A. F. H., Möhlig, M., et al. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00020.2010 · Cited by 58
Relation between fibroblast growth factor–21, adiposity, metabolism, and weight reduction
Mai, K., Schwarz, F., Bobbert, T., Andres, J., Aßmann, A., Pfeiffer, A. F. H., & Spranger, J. (2010) · Metabolism · doi:10.1016/j.metabol.2010.02.016 · Cited by 58
Allard, C., Bonnet, F., Xu, B., Coons, L. A., Albarado, D. C., Hill, C. M., Fagherazzi, G., Korach, K. S., Levin, E. R., Lefante, J. J., et al. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.02.002 · Cited by 58
Increased Placental Expression of Fibroblast Growth Factor 21 in Gestational Diabetes Mellitus
Nitert, M. D., Barrett, H. L., Kubala, M. H., Scholz‐Romero, K., Denny, K. J., Woodruff, T. M., McIntyre, D. H., & Callaway, L. K. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2581 · Cited by 57
Fougerat, A., Bruse, J., Polizzi, A., Montagner, A., Guillou, H., & Wahli, W. (2024) · Progress in Lipid Research · doi:10.1016/j.plipres.2024.101303 · Cited by 56
“In healthy humans, circulating FGF21 is only induced by prolonged fasting (7 – 10 days) and is not required for fasting-induced ketogenesis [188 – 190].”
Domingo, P., Gallego-Escuredo, J. M., Domingo, J. C., Gutiérrez, M. D. M., Mateo, G. M., Fernández, I., Vidal, F., Giralt, M., & Villarroya, F. (2010) · AIDS · doi:10.1097/qad.0b013e3283400088 · Cited by 53
“Some studies have indicated that FGF21 is expressed in human adipose tissue [16,17] thus it may be that lipoatrophic subcutaneous fat or the enlarged visceral adipose tissue depots are sources of increased FGF21 levels.”
BackgroundHashidume, T., Kato, A., Tanaka, T., Miyoshi, S., Itoh, N., Nakata, R., Inoue, H., Oikawa, A., Nakai, Y., Shimizu, M., et al. (2016) · Scientific Reports · doi:10.1038/srep28183 · Cited by 52
Zarei, M., Aguilar-Recarte, D., Palomer, X., & Vázquez‐Carrera, M. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154342 · Cited by 49
Hepatic hormone FGF21 and its analogues in clinical trials
Shao, W., & Jin, T. (2021) · Chronic Diseases and Translational Medicine · doi:10.1016/j.cdtm.2021.08.005 · Cited by 49
Early investigational drugs targeting PPAR-α for the treatment of metabolic disease
Liu, Z.-M., Hu, M., Chan, P., & Tomlinson, B. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.1006359 · Cited by 45
“Circulating FGF21 in humans increased significantly in response to treatment with PPAR-a and PPAR-d, but not PPAR-g agonists and this may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds [45].”
BackgroundMetabolic actions of fibroblast growth factor 21
Ramos, D. C., Aguilar-Salinas, C. A., & Gomez-Perez, F. J. (2012) · Current Opinion in Pediatrics · doi:10.1097/mop.0b013e3283557d22 · Cited by 46
Stemmer, K., Zani, F., Habegger, K. M., Neff, C., Kotzbeck, P., Bauer, M., Yalamanchilli, S., Azad, A., Lehti, M., Martins, P. J. F., et al. (2015) · Diabetologia · doi:10.1007/s00125-015-3668-7 · Cited by 44
“Profound variations in body weight, fat mass and glucose and lipid metabolism in various strains of Fgf21-knockout (Fgf21-KO) mice [12–16] and the wide range of serum FGF21 concentrations in humans challenged the relevance of endogenous FGF21 in metabolism [17–19].”
BackgroundKim, E. R., Kim, S. R., Cho, W., Lee, S., Kim, S. H., Kim, J. H., Choi, E., Kim, J., Yu, J., Lee, B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.843520 · Cited by 44
Fibroblast growth factor 21 in heart failure
Tucker, W., Tucker, B., Rye, K., & Ong, K. L. (2022) · Heart Failure Reviews · doi:10.1007/s10741-022-10268-0 · Cited by 44
Benetti, E., Mastrocola, R., Rogazzo, M., Chiazza, F., Aragno, M., Fantozzi, R., Collino, M., & Minetto, M. A. (2013) · Mediators of Inflammation · doi:10.1155/2013/509502 · Cited by 44
“Our observation is also in keeping with a previous study showing that circulating FGF-21 levels consistently increase in human subjects in response to pharmacological activation of PPAR-δ [50].”
ResultHeme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency
Zarei, M., Barroso, E., Leiva, R., Barniol‐Xicota, M., Pujol, E., Escolano, C., Vázquez, S., Palomer, X., Pardo, V., González‐Rodríguez, Á., et al. (2016) · Diabetes · doi:10.2337/db16-0155 · Cited by 42
Curcumin and dietary polyphenol research: beyond drug discovery
Jin, T. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.179 · Cited by 43
Fibroblast growth factor 21 in metabolic syndrome
Yang, M., Liu, C., Jiang, N., Liu, Y., Luo, S., Li, C., Zhao, H., Han, Y., Chen, W., Li, L., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1220426 · Cited by 40
“A similar result was also observed in that participants treated with PPAR a agonists showed higher circulating FGF21 levels (30).”
ResultThe potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus (T2DM)
Al-Kuraishy, H. M., Al-Gareeb, A. I., Saad, H. M., & Batiha, G. E. (2023) · Inflammopharmacology · doi:10.1007/s10787-023-01255-4 · Cited by 39
“Thus, PPAR-α agonists can enhance FGF21 expression (Christodoulides et al. 2009).”
BackgroundElevated Serum Fibroblast Growth Factor 21 in Humans with Acute Pancreatitis
Shenoy, V. K., Beaver, K. M., Fisher, F. M., Singhal, G., Dushay, J. R., Maratos–Flier, E., & Flier, S. N. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164351 · Cited by 36
Metabolic actions of FGF21: molecular mechanisms and therapeutic implications
Ge, X., Wang, Y., Lam, K. S., & Xu, A. (2012) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2012.06.011 · Cited by 35
Protein Appetite at the Interface between Nutrient Sensing and Physiological Homeostasis
Khan, M. S. H., Spann, R. A., Münzberg, H., Yu, S., Albaugh, V. L., He, Y., Berthoud, H., & Morrison, C. D. (2021) · Nutrients · doi:10.3390/nu13114103 · Cited by 35
“Interestingly, these effects did not readily translate to humans [100,101].”
BackgroundNutritional Ketosis as a Potential Treatment for Alcohol Use Disorder
Mahajan, V. R., Elvig, S. K., Vendruscolo, L. F., Koob, G. F., Darcey, V. L., King, M. T., Kranzler, H. R., Volkow, N. D., & Wiers, C. E. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.781668 · Cited by 34
Wu, C., Gilroy, R. K., Taylor, R. M., Olyaee, M. S., Abdulkarim, B., Forster, J., O’Neil, M. F., Damjanov, I., & Wan, Y. Y. (2010) · Hepatology · doi:10.1002/hep.24645 · Cited by 33
Huang, T., Linden, M. A., Fuller, S. E., Goldsmith, F., Simon, J., Batdorf, H. M., Scott, M. C., Essajee, N. M., Brown, J. M., & Noland, R. C. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00410.2020 · Cited by 36
Higher serum levels of fibroblast growth factor 21 in old patients with cachexia
Franz, K., Ost, M., Otten, L., Herpich, C., Coleman, V., Endres, A., Klaus, S., Müller‐Werdan, U., & Norman, K. (2018) · Nutrition · doi:10.1016/j.nut.2018.11.004 · Cited by 31
Whytock, K. L., Carnero, E. A., Vega, R. B., Tillner, J., Bock, C., Chivukula, K., Yi, F., Meyer, C., Smith, S. R., & Sparks, L. M. (2021) · Obesity · doi:10.1002/oby.23141 · Cited by 30
“The systemic peptide hormone FGF21 has been linked to increased EE and enhanced fatty acid oxidation following a ketogenic diet in rodents (23); however, this has not been replicated in human studies (24).”
BackgroundFGF21 signalling pathway and metabolic traits – genetic association analysis
Kaess, B. M., Barnes, T. A., Stark, K. J., Charchar, F. J., Waterworth, D. M., Song, K. S., Wang, W. Y. S., Vollenweider, P., Waeber, G., Mooser, V., et al. (2010) · European Journal of Human Genetics · doi:10.1038/ejhg.2010.130 · Cited by 30
Liao, Y., Wang, Y.-H., Wu, C.-Y., Hsu, F.-Y., Chien, C.-Y., & Lee, Y.-C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062934 · Cited by 29
“In contrast, a KD did not increase FGF21 serum levels in humans [46,48,50].”
Murphy, M., Samms, R. J., Warner, A., Bolborea, M., Barrett, P., Fowler, M. J., Brameld, J. M., Tsintzas, K., Kharitonenkov, A., Adams, A. C., et al. (2012) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02383.x · Cited by 29
Self-citationFibroblast Growth Factor 21: A Novel Metabolic Regulator
Seo, J. A., & Kim, N. H. (2012) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2012.36.1.26 · Cited by 27
“In fact, the effects of ketogenic diet on circulating FGF21 concentrations in humans are inconsistent [5,17,18] and circulating FGF21 concentrations in humans showed a broad 250-fold interindividual variation [5].”
BackgroundFibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior
Wu, C.-T., CHAFFIN, A. T. B., & Ryan, K. K. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030580 · Cited by 24
“Pharmacological activation of PPARα robustly induces FGF21 in humans [24,28,30], but the effect of KD in activating PPARα and increasing circulating FGF21 in humans is inconsistent at best [26,28,30].”
BackgroundPérez‐Martí, A., Sandoval, V., Marrero, P. F., Haro, D., & Relat, J. (2016) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2016-0034 · Cited by 24
Estrogen-Wnt signaling cascade regulates expression of hepatic fibroblast growth factor 21
Badakhshi, Y., Shao, W., Liu, D., Tian, L., Pang, J., Gu, J., Hu, J., & Jin, T. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00638.2020 · Cited by 23
Plasma mannose-binding lectin is stimulated by PPARα in humans.
Rakhshandehroo, M., Stienstra, R., de Wit, N. D., Bragt, M., Haluzík, M., Mensink, R., Müller, M., & Kersten, S. (2012) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00299.2011 · Cited by 24
Liu, X., Zhang, Y., Ma, C., Lin, J., & Du, J. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07142-5 · Cited by 22
“Recently, seven to ten days of starvation is required for the circulating FGF21 concentration to increase in humans [36, 37], whereas fasting for up to 72 h does not change FGF21 levels [38, 39].”
BackgroundMcCullough, D., Harrison, T., Boddy, L. M., Enright, K. J., Amirabdollahian, F., Schmidt, M., Doenges, K., Quinn, K. D., Reisdorph, N. A., Mazidi, M., et al. (2022) · Nutrients · doi:10.3390/nu14183691 · Cited by 22
“[76] in which 7 subjects (5 diabetic) reduced their FGF21 levels (p < 0.”
BackgroundChen, H., Dardik, B. N., Qiu, L., Ren, X., Caplan, S. L., Burkey, B. F., Boettcher, B. R., & Gromada, J. (2010) · Endocrinology · doi:10.1210/en.2009-1366 · Cited by 22
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
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
