FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPARα and PPARγ Agonists
Open accessAbstract
Results of prior studies suggest that fibroblast growth factor 21 (FGF21) may be involved in bone turnover and in the actions of peroxisome proliferator-activated receptor (PPAR) α and γ in mice. We have conducted independent studies to examine the effects of FGF21 on bone homeostasis and the role of FGF21 in PPARα and γ actions. High-fat-diet-induced obesity (DIO) mice were administered vehicle or recombinant human FGF21 (rhFGF21) intraperitoneally at 0 (vehicle), 0.1, 1, and 3 mg/kg daily for 2 weeks. Additional groups of DIO mice received water or 10 mg/kg rosiglitazone daily. Mice treated with rhFGF21 or rosiglitazone showed expected metabolic improvements in glucose, insulin, and lipid levels. However, bone loss was not detected in rhFGF21-treated mice by dual-energy X-ray absorptiometry (DXA), micro-CT, and histomorphometric analyses. Mineral apposition rate, a key bone formation parameter, was unchanged by rhFGF21, while significantly decreased by rosiglitazone in DIO mice. Bone resorption markers, OPG/RANKL mRNA expression, and histological bone resorption indices were unchanged by rhFGF21 or rosiglitazone. Bone marrow fat was unchanged by rhFGF21, while increased by rosiglitazone. Furthermore, FGF21 knockout mice did not show high bone mass phenotype. Treatment with PPARα or PPARγ agonists caused similar metabolic effects in FGF21 knockout and wild-type mice. These results contrast with previous findings and suggest that FGF21 is not critical for bone homeostasis or actions of PPARα and PPARγ. © 2016 American Society for Bone and Mineral Research.
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In mice, FGF21 has been reported to promote bone loss, but this effect has not been independently validated in rodents or obese non-human primates.
“In mice, FGF21 has been reported to promote bone loss96,97, but this effect has not been independently validated in rodents98 or obese non-human primates99.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [98]
In mice, FGF21 has been reported to promote bone loss, but this finding could not be replicated.
“In mice, FGF21 has been reported to promote bone loss (134, 135); however, this finding could not be replicated (80).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [80]
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Phimphilai, M., Phrommintikul, A., Wongcharoen, W., Hengjeerajarus, N., Karndumri, K., Chattipakorn, N., & Chattipakorn, S. C. (2025) · Scientific Reports · doi:10.1038/s41598-025-15104-7
Liu, Z., Chen, B., Han, W., Cheng, L., Li, X., Zhang, Y., Wang, D., Li, Y., Wang, Y., wang, X., et al. (2026) · Materials & Design · doi:10.1016/j.matdes.2026.115991
Self-citationExercise Modulates the Osteoimmune Axis: Myokine‐Mediated Mechanisms in Diabetic Bone Disease
Wu, C.-L., Zou, J., & Yuan, Y. (2026) · Diabetes/Metabolism Research Reviews · doi:10.1002/dmrr.70245
- Authors
- Li, X., Stanislaus, S., Asuncion, F., Niu, Q.-T., Chinookoswong, N., Villasenor, K., Wang, J., Wong, P., Boyce, R., Dwyer, D., Han, C.-Y., Chen, M. M., Liu, B., Stolina, M., Ke, H. Z., Ominsky, M. S., Véniant, M. M., & Xu, J.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Li, Xiaodong
- Xu, Jing
- ORCID
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-08-09
- Volume
- 32
- Issue
- 4
- Pages
- 834-845
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2480504285
- Cited by
- 61
- References
- 29
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 1
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- FGF21, bone homeostasis, PPARα agonist, PPARγ agonists, rosiglitazone, high-fat diet-induced obesity, bone loss, bone formation, bone resorption, bone marrow fat, FGF21 knockout mice, mineral apposition rate
- MeSH terms
- Rosiglitazone, Animals, Dietary Fats, Fibroblast Growth Factors, Gene Expression Regulation, Glucose, Homeostasis, Humans, Insulin, Male, Obesity, Bone Density, Mice, Knockout, Thiazolidinediones, PPAR alpha, PPAR gamma, Mice, Osteoprotegerin, RANK Ligand
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 ›
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