Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway
Open accessAbstract
Aims/hypothesis This study investigated fibroblast growth factor 21 (FGF21)-mediated cardiac protection against apoptosis caused by diabetic lipotoxicity and explored the protective mechanisms involved.Methods Cardiac Fgf21 mRNA expression was examined in a diabetic mouse model using real-time PCR. After pre-incubation of palmitate-treated cardiac H9c2 cells and primary cardiomyocytes with FGF21 for 15 h, apoptosis and Fgf21-induced cell-survival signalling were investigated using small interfering (si)RNA and/or pharmacological inhibitors. We also examined the cardiac apoptotic signalling and structural and functional indices in wild-type and Fgf21-knockout (Fgf21-KO) diabetic mice.Results In a mouse model of type 1 diabetes, cardiac Fgf21 expression was upregulated about 40-fold at 2 months and 3-1.5-fold at 4 and 6 months after diabetes. FGF21 significantly reduced palmitate-induced cardiac apoptosis. Mechanistically, palmitate downregulated, but FGF21 upregulated, phosphorylation levels of extracellular signal-regulated kinase (ERK)1/2, mitogen-activated protein kinase 14 (p38 MAPK) and AMP-activated protein kinase (AMPK). Inhibition of each kinase with its inhibitor and/or siRNA revealed that FGF21 prevents palmitate-induced cardiac apoptosis via upregulating the ERK1/2-dependent p38 MAPK-AMPK signalling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic or fatty-acid-infused mice significantly prevented cardiac apoptosis and reduced inactivation of ERK1/2, p38 MAPK and AMPK and prevented cardiac remodelling and dysfunction. The Fgf21-KO mice were more susceptible to diabetes-induced cardiac apoptosis, and this could be prevented by administration of FGF21. Deletion of Fgf21 did not further exacerbate cardiac dysfunction.Conclusions/interpretation These results demonstrate that FGF21 prevents lipid- or diabetes-induced cardiac apoptosis by activating the ERK1/2-p38 MAPK-AMPK pathway. FGF21 may be a therapeutic target for the treatment of diabetes-related cardiac damage.
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Recombinant FGF21 or FGF21 variants have beneficial metabolic effects in mice; only a small trend toward glucose lowering was reported in humans.
“Extensive efforts have also been made with the use of recombinant FGF21 or FGF21 variants as potential therapy, due to beneficial metabolic effects observed in mice 152, 153; however, only a small trend toward glucose lowering was reported in humans 154.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [152]
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- Authors
- Zhang, C., Huang, Z., Gu, J., Yan, X., Lu, X., Zhou, S., Wang, S., Shao, M., Zhang, F., Cheng, P., Feng, W., Tan, Y., & Li, X.
- Affiliations
- Wenzhou Medical University (CN)
- University of Louisville (US)
- Corresponding author
- Tan, Yi
- Li, Xiaokun
- ORCID
- Venue
- Diabetologia
- Published
- 2015-06-04
- Volume
- 58
- Issue
- 8
- Pages
- 1937-1948
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W565001682
- Cited by
- 113
- References
- 38
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 11 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 12 · 2017: 16 · 2016: 16 · 2015: 3
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association (81000294, QTJ13007, QTJ13005, 2012ZX09103-301-016, 81273509, 1-13-JF-53, 81370917)
- Wenzhou Medical University (1-13-JF-53, 2012ZX09103-301-016, QTJ13007, 81370917, QTJ13005, 81273509, 81000294)
- National Natural Science Foundation of China (81370917, 2012ZX09103-301-016, 32500301, 81102486, 81000294, QTJ13005, 81273509, 2010R50042, 81473261, 1-13-JF-53, QTJ 13007)
- Chinese Diabetes Society
- National Institute on Alcohol Abuse and Alcoholism (R21AA022416)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- FGF21, cardiac apoptosis, type 1 diabetes, diabetic cardiomyopathy, ERK1/2, p38 MAPK, AMPK, cardiac remodeling, FGF21 knockout mice
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Fibroblast Growth Factors, Heart, Myocardium, Phosphorylation, Apoptosis, Mice, Knockout, MAP Kinase Signaling System, Mice
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