The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue
Open accessAbstract
FGF21 is a multifunctional metabolic regulator. The co-factor βKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.
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FGF21 signals to a receptor complex comprised of FGFR1c and KLB.
“FGF21 signals to a receptor complex comprised of FGF receptor 1c (FGFR1c) and its co-receptor β-klotho (KLB) [[143], [144], [145], [146]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [145]
Both Fgfr1fl/fl;ap2-Cre and Klbfl/fl;ap2-Cre mice are refractory to the acute insulin-sensitizing effects of FGF21.
“Both Fgfr1fl/fl;ap2-Cre and Klbfl/fl;ap2-Cre mice were refractory to the acute insulin-sensitizing effects of FGF21 (4, 27).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [4]
Adipose-specific Fgfr1 knockout mice (Fgfr1fl/fl;Adiponectin-Cre) respond to chronic FGF21 administration similarly to control mice.
“Consistent with these results, adipose-specific Fgfr1 knockout mice (Fgfr1fl/fl;Adiponectin-Cre) were also recently shown to respond to chronic FGF21 administration similarly to control mice (17) in contrast to the results obtained with Fgfr1fl/fl;ap2-Cre mice (4).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [4]
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Self-citation
- Authors
- Adams, A. C., Yang, C., Coskun, T., Cheng, C. C., Gimeno, R. E., Luo, Y., & Kharitonenkov, A.
- Affiliations
- Eli Lilly (United States) (US)
- Texas A&M Health Science Center (US)
- Corresponding author
- Kharitonenkov, Alexei
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 2
- Issue
- 1
- Pages
- 31-37
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC3757657
- OpenAlex
- W2050259739
- Cited by
- 266
- References
- 23
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 14 · 2023: 11 · 2022: 21 · 2021: 15 · 2020: 19 · 2019: 20 · 2018: 16 · 2017: 26 · 2016: 38 · 2015: 30 · 2014: 19 · 2013: 17 · 2012: 3
- FWCI
- 8.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly
- Susan Komen Foundation
- John S. Dunn Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- FGF21, FGFR1, adipose tissue, β-Klotho, FGF19, FGF receptor signaling, tissue-specific gene expression, glucose homeostasis, insulin, triglycerides, adipokines, energy expenditure, free fatty acids, metabolic regulation
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