FGF21 Requires βklotho to Act In Vivo
Open accessAbstract
FGF21 has gradually become a focal point in metabolic research given its intriguing and complex biology and relevance to drug discovery. Despite the large amount of accumulated data, there remains a dearth of understanding of FGF21 physiology at the molecular/whole organism level. The scaffold protein βklotho (KLB) has previously been demonstrated in vitro to function as a co-factor permitting FGF21 mediated FGF receptor activation. However, the requirement for KLB in the propagation of FGF21 action in living animals has yet to be evaluated. To answer this question, we tested FGF21 in mice with total body ablation of KLB (KLBKO) and found no detectable activity. Firstly, we demonstrate that the disruption of KLB entirely abrogates acute FGF21 signaling in adipose tissue. We go on to show that this signaling defect translates to the absence of FGF21 mediated metabolic improvements in DIO mice. Indeed, KLBKO mice are totally refractory to FGF21-induced normalization of glucose homeostasis, attenuation of dyslipidemia, elevation of energy expenditure and weight loss. The lack of FGF21-driven effects was further substantiated at the transcriptional level with no FGF21 target gene signature detectable in adipose tissue and liver of KLBKO animals. Taken together our data show that KLB is a vital component of the FGF21 in vivo signaling machinery and is critically required for FGF21 action at the whole organism level.
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Loss of KLB abolishes all effects of FGF21 in vitro and in vivo.
“loss of KLB abolishes all effects of FGF21 in vitro and in vivo46,53–56.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [55]
FGF21 functions in target tissues that express FGFR1c and the obligate coreceptor β-klotho.
“FGF21 functions in target tissues that express the traditional FGF receptor FGFR1c and the obligate coreceptor β-klotho (2, 27, 71, 99, 124, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [2]
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- Authors
- Adams, A. C., Cheng, C. C., Coskun, T., & Kharitonenkov, A.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Kharitonenkov, Alexei
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-11-27
- Volume
- 7
- Issue
- 11
- Pages
- e49977
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3507945
- OpenAlex
- W2086624706
- Cited by
- 181
- References
- 38
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 9 · 2023: 13 · 2022: 14 · 2021: 12 · 2020: 12 · 2019: 21 · 2018: 14 · 2017: 14 · 2016: 18 · 2015: 18 · 2014: 7 · 2013: 12
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- 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 › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- FGF21, β-Klotho, KLB, FGF receptor signaling, adipose tissue, glucose homeostasis, dyslipidemia, energy expenditure, weight loss, diet-induced obesity, metabolic signaling
- MeSH terms
- Klotho Proteins, Animals, Energy Metabolism, Female, Fibroblast Growth Factors, Gene Expression Regulation, Liver, Male, Membrane Proteins, Mice, Knockout, Mice, Adipose Tissue, White
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