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Cited by 181Fibroblast Growth Factor ResearchAdipokines, Inflammation, and Metabolic DiseasesParathyroid Disorders and Treatments

The DOI matches its Crossref record; 37 of the 38 references it cites were found in a registry or an index.

FGF21 Requires βklotho to Act In Vivo

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Adams, Andrew C., Cheng, Christine C., Coskun, Tamer, Kharitonenkov, Alexei·2012·PLoS ONE
DOI 10.1371/journal.pone.0049977PMC PMC3507945
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Abstract

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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Crossref · 10.1371/journal.pone.0049977

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Figures

Figure 1 Expression of FGFR/Klotho receptor components (A–F), KLB protein expression in liver and WAT (G). Induction of immediate early genes EGR-1 (H) and cFOS (I) expression in WAT of WT and KLBKO animals following acute FGF21 treatment. Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.
Figure 1 Expression of FGFR/Klotho receptor components (A–F), KLB protein expression in liver and WAT (G). Induction of immediate early genes EGR-1 (H) and cFOS (I) expression in WAT of WT and KLBKO animals following acute FGF21 treatment. Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.CC BY · PubMed Central
Figure 2 Following chronic FGF21 treatment we assessed weight loss (A), fat mass loss (B), food intake (C) and energy expenditure in WT (D) and KLBKO mice (E). Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.
Figure 2 Following chronic FGF21 treatment we assessed weight loss (A), fat mass loss (B), food intake (C) and energy expenditure in WT (D) and KLBKO mice (E). Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.CC BY · PubMed Central
Figure 3 To determine the effect of chronic FGF21 on circulating hormones and metabolites we measured plasma glucose (A), insulin (B), cholesterol (C), β-Hydroxybutyrate (D), adiponectin (E). Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.
Figure 3 To determine the effect of chronic FGF21 on circulating hormones and metabolites we measured plasma glucose (A), insulin (B), cholesterol (C), β-Hydroxybutyrate (D), adiponectin (E). Statistical analysis was performed using one-way ANOVA, followed by Dunnett’s multiple comparisons test where appropriate. Differences were considered significant when P≤0.05.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Holland WL, Adams AC, Bauer S, Brozinick J, Kharitonenkov A, <etal>et al</etal>. (2012) Adiponectin is Critical for Acute Insulin Sensitizing Effects of FGF-21. International Symposium on Adiponectin Biology and Medicine. Tomakomai, Japan: Nature Publishing Group.
  2. AC Adams, 2012, Fundamentals of FGF19 & FGF21 action in vitro and in vivo, PLoS One, 7, e38438, 10.1371/journal.pone.0038438 · DOI · Paper page

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Metadata

Authors
Adams, A. C., Cheng, C. C., Coskun, T., & Kharitonenkov, A.
Affiliations
Eli Lilly (United States) (US)
Corresponding author
Kharitonenkov, Alexei
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-11-27
Volume
7
Issue
11
Pages
e49977
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0049977
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
Licence
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 › Endocrinology, Diabetes and Metabolism › 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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