Novel Insights into the Cardio-Protective Effects of FGF21 in Lean and Obese Rat Hearts
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AIMS: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. METHODS AND RESULTS: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. CONCLUSION: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia.
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FGF21 is expressed and released into the general circulation by several tissues such as the liver, white adipose tissue, brown adipose tissue, and the heart.
“The metabolic regulator FGF21 is expressed and released into the general circulation by several tissues such as the liver, WAT, BAT, and the heart.7, 8, 9, 10, 11”
From Fibroblast growth factor 21 controls mitophagy and muscle mass (2019) · cites this paper as [9]
KLB expression is primarily restricted to specific metabolic tissues (liver, pancreas, adipose) and lower in brain; KLB is not expressed in muscle.
“KLB expression is primarily restricted to specific metabolic tissues (for example, the liver, pancreas and adipose tissue)5, and lower expression is observed in the brain22,48–50. Despite some reports to the contrary51,52, KLB is not expressed in muscle5,41.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [51]
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References 46 · Cited by 124
- Authors
- Patel, V., Adya, R., Chen, J., Ramanjaneya, M., Bari, M. F., Bhudia, S. K., Hillhouse, E. W., Tan, B. K., & Randeva, H. S.
- Affiliations
- University of Warwick (GB)
- Weill Cornell Medical College in Qatar (QA)
- Corresponding author
- Randeva, Harpal S.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-02-03
- Volume
- 9
- Issue
- 2
- Pages
- e87102
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3911936
- OpenAlex
- W2066046884
- Cited by
- 124
- References
- 46
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 11 · 2020: 8 · 2019: 13 · 2018: 9 · 2017: 15 · 2016: 9 · 2015: 14 · 2014: 3
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Greater South Information System
- Funders
- University of Warwick
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- FGF21, cardioprotection, obesity, myocardial ischemia, β-Klotho, FGFR1, cardiomyocytes, PI3K/Akt signaling, AMPK, ERK1/2, RORα, autocrine and paracrine signaling, cardiac function, hypoxia
- MeSH terms
- Animals, Cells, Cultured, Fibroblast Growth Factors, Heart, Humans, Male, Myocardium, Obesity, Blotting, Western, Signal Transduction, Gene Expression, Myocardial Ischemia, Rats, Wistar, Microscopy, Confocal, Protective Agents, Reverse Transcriptase Polymerase Chain Reaction, Myocytes, Cardiac, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Rats, AMP-Activated Protein Kinases, Nuclear Receptor Subfamily 1, Group F, Member 1, Phosphatidylinositol 3-Kinase, In Vitro Techniques
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