The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
Circulating FGF21 proteolytic processing mediated by fibroblast activation protein
Open accessAbstract
Fibroblast growth factor 21 (FGF21), a hormone implicated in the regulation of glucose homoeostasis, insulin sensitivity, lipid metabolism and body weight, is considered to be a promising therapeutic target for the treatment of metabolic disorders. Despite observations that FGF21 is rapidly proteolysed in circulation rending it potentially inactive, little is known regarding mechanisms by which FGF21 protein levels are regulated. We systematically investigated human FGF21 protein processing using mass spectrometry. In agreement with previous reports, circulating human FGF21 was found to be cleaved primarily after three proline residues at positions 2, 4 and 171. The extent of FGF21 processing was quantified in a small cohort of healthy human volunteers. Relative abundance of FGF21 proteins cleaved after Pro-2, Pro-4 and Pro-171 ranged from 16 to 30%, 10 to 25% and 10 to 34%, respectively. Dipeptidyl peptidase IV (DPP-IV) was found to be the primary protease responsible for N-terminal cleavages after residues Pro-2 and Pro-4. Importantly, fibroblast activation protein (FAP) was implicated as the protease responsible for C-terminal cleavage after Pro-171, rendering the protein inactive. The requirement of FAP for FGF21 proteolysis at the C-terminus was independently demonstrated by in vitro digestion, immunodepletion of FAP in human plasma, administration of an FAP-specific inhibitor and by human FGF21 protein processing patterns in FAP knockout mouse plasma. The discovery that FAP is responsible for FGF21 inactivation extends the FGF21 signalling pathway and may enable novel approaches to augment FGF21 actions for therapeutic applications.
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?
In the citing paper
“Notably, human but not mouse FGF21 is cleaved and processed by FAP, because mouse FGF21 possesses a single–amino acid difference in the stringent FAP-recognition motif42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [43]
In the citing paper
“FGF21 is also subject to proteolytic cleavage by the serine proteases fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV)42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [43]
In the citing paper
“Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP) (29, 150).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [150]
In the citing paper
“Interestingly, mouse FGF21 is neither cleaved nor inactivated by FAP because mouse FGF21 has a glutamate residue at the corresponding glycine residue at position 170, which disrupts the stringent glycine–proline sequence required for FAP-mediated cleavage (29, 150).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [150]
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
IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040
Ogurtsova, K., Fernandes, J. D. D. R., Huang, Y., Linnenkamp, U., Guariguata, L., Cho, N. H., Cavan, D. A., Shaw, J. E., & Makaroff, L. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.03.024 · Cited by 7,138
IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030
Whiting, D. R., Guariguata, L., Weil, C., & Shaw, J. E. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.10.029 · Cited by 4,018
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885
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
Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease
Itoh, N., & Ornitz, D. M. (2010) · The Journal of Biochemistry · doi:10.1093/jb/mvq121 · Cited by 726
Scanlan, M. J., Raj, B. K. M., Calvo, B. F., Garin‐Chesa, P., Sanz-Moncasi, M. P., Healey, J. H., Old, L. J., & Rettig, W. J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.12.5657 · Cited by 577
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
Biological actions and therapeutic potential of the glucagon-like peptides
Drucker, D. J. (2002) · Gastroenterology · doi:10.1053/gast.2002.31068 · Cited by 509
Hamson, E., Keane, F. M., Tholen, S., Schilling, O., & Gorrell, M. D. (2014) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201300095 · Cited by 501
Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice
Santos, A., Jung, J. J., Aziz, N., Kissil, J. L., & Puré, E. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38988 · Cited by 436
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–124 of 124
Sporadic Pancreatic Cancer: Glucose Homeostasis and Pancreatogenic Type 3 Diabetes
Škrha, J., Fric, P., Bušek, P., Škrha, P., & Šedo, A. (2018) · InTech eBooks · doi:10.5772/intechopen.75740 · Cited by 3
Xi, C., Fazio, A. D., Nadvi, N. A., Xiang, M. S. W., Zhang, H. E., Deshpande, C. N., Chen, Y., Tabar, M. S., Wang, X. M., Bailey, C. G., et al. (2021) · Protein Expression and Purification · doi:10.1016/j.pep.2021.105833 · Cited by 2
Overexpression and Purification of Mitogenic and Metabolic Fibroblast Growth Factors
Phan, P., Sonnaila, S., Ternier, G., Edirisinghe, O., Okoto, P. S., & Kumar, T. K. S. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3666-4_10 · Cited by 2
Effect of exercise on Fibroblast Growth Factor 21 levels in healthy males and females
Peterson, M. N., Richardson, K. A., & Funderburk, L. (2025) · PLoS ONE · doi:10.1371/journal.pone.0321738 · Cited by 2
GH replacement therapy in adults stimulates fibroblast activation protein-α activity
Bæk, A., Pedersen, A. K. N., Billeskov, T. B., Dollerup, O. L., Arlien-Søborg, M. C., Jessen, N., Bjerre, M., & Jørgensen, J. O. L. (2025) · European Journal of Endocrinology · doi:10.1093/ejendo/lvaf244 · Cited by 1
Serum fibroblast growth factor 21 is a novel biomarker of cachexia in chronic liver disease
Tanaka, T., Suda, G., Ohara, M., Maehara, O., Yoda, T., Fu, Q., Yang, Z., Yasuura, N., Meno, A., Sasaki, T., et al. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1730695 · Cited by 1
Fibroblast Activation Protein (FAP): A Key Modulator of the Cancer Microenvironment
Mousavi, M. J., Karami, J., Alimohammadi, M., Solaymani‐Mohammadi, F., & Rezaei, N. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_357-1 · Cited by 1
Bayoumi, A. (2020) · The Sydney eScholarship Repository (The University of Sydney)
Structural basis of FGF23 hormone signaling
Zinkle, A., Goetz, R. M., Chen, L., & Mohammadi, M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-818036-5.00002-1
Regulation of the organokines FGF21 and chemerin by diet
Seebeck, N. (2020) · publish.UP (University of Potsdam) · doi:10.25932/publishup-47114
ADME of Biologicals and New Therapeutic Modalities
Foti, R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00141-9
Dufresne, J., Bowden, P., Thavarajah, T., Florentinus-Mefailoski, A., Chen, Z. Z., Tucholska, M., Norzin, T., Ho, M. T., Phan, M., Mohamed, N., et al. (2021) · doi:10.32920/14638233.v1
Dufresne, J., Bowden, P., Thavarajah, T., Florentinus-Mefailoski, A., Chen, Z. Z., Tucholska, M., Norzin, T., Ho, M. T., Phan, M., Mohamed, N., et al. (2021) · doi:10.32920/14638233
Dufresne, J., Bowden, P., Thavarajah, T., Florentinus-Mefailoski, A., Chen, Z. Z., Tucholska, M., Norzin, T., Ho, M. T., Phan, M., Mohamed, N., et al. (2022) · doi:10.32920/14638233.v2
Fibroblast Activation Protein (FAP): A Key Modulator of the Cancer Microenvironment
Mousavi, M. J., Karami, J., Alimohammadi, M., Solaymani‐Mohammadi, F., & Rezaei, N. (2025) · Springer eBooks · doi:10.1007/978-3-032-00761-2_357
Xiao, H., Ding, Z., Liu, C., He, X., & Tao, Y. (2025) · Experimental Biology and Medicine · doi:10.3389/ebm.2025.10612
Ahmed, T. A., Ahmed, S. M., Elkhenany, H. A., El-Desouky, M. A., Magdeldin, S., Osama, A., Anwar, A. M., Mohamed, I. K., Abdelgawad, M. E., Hanna, D. H., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26678843
Ahmed, T. A., Ahmed, S. M., Elkhenany, H. A., El-Desouky, M. A., Magdeldin, S., Osama, A., Anwar, A. M., Mohamed, I. K., Abdelgawad, M. E., Hanna, D. H., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26678846
Zhang, Y., Liu, D., Lu, Y., Kang, P., Liu, X., Wang, Q., Chen, A., Cheng, D., Wu, L., Li, Q., et al. (2026) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2024.0814
Zhao, S., Ji, Z., Wang, Y., Li, J., He, Y., Shen, J., Liu, C., Wang, L., Ma, X., Wang, S., et al. (2026) · iScience · doi:10.1016/j.isci.2026.116260
Zheng, J., Han, B., Wang, S. M., Dong, L., Jin, J., Wang, K., Hai, D., Yang, M., Xu, Y., Pan, J., et al. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118136
Beneficial Hepatokines in MASLD/MASH: Therapeutic Potentials and Drug Delivery Challenges
Amatya, R., Min, K. A., & Shin, M. C. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27167118
Advances in FGF/FGFR Signaling: Implications for Disease and Therapy
Song, M., Liu, X., Xiao, Y., Li, Y., & Zhao, H. (2026) · MedComm · doi:10.1002/mco2.70922
BindingDB (2022) · UC San Diego · doi:10.7270/q2pn999j
Metadata
- Authors
- Zhen, E. Y., Jin, Z., Ackermann, B. L., Thomas, M. K., & Gutierrez, J. A.
- Affiliations
- Tailored Therapeutics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, U.S.A.
- Eli Lilly (United States) (US)
- ORCID
- Thomas, Melissa K.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2016-02-24
- Volume
- 473
- Issue
- 5
- Pages
- 605-614
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC4764976
- OpenAlex
- W2292257555
- Cited by
- 123
- References
- 54
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 16 · 2022: 9 · 2021: 17 · 2020: 16 · 2019: 7 · 2018: 15 · 2017: 12 · 2016: 7
- FWCI
- 4.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Biochemical Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- University of Pennsylvania
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- FGF21, fibroblast activation protein, proteolytic processing, proteolytic cleavage, dipeptidyl peptidase IV, FAP inhibitors, metabolic disorders, glucose homeostasis, insulin sensitivity, lipid metabolism
- MeSH terms
- Animals, Fibroblasts, Humans, Insulin Resistance, Protein Processing, Post-Translational, Lipid Metabolism, Proteolysis
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
