βKlotho is required for metabolic activity of fibroblast growth factor 21
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine factor that stimulates glucose uptake in adipocytes. Here, we show that FGF21 activity depends on βKlotho, a single-pass transmembrane protein whose expression is induced during differentiation from preadipocytes to adipocytes. βKlotho physically interacts with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF21 and activate the MAP kinase cascade. Knockdown of βKlotho expression by siRNA in adipocytes diminishes glucose uptake induced by FGF21. Importantly, administration of FGF21 into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without βKlotho expression. Thus, βKlotho functions as a cofactor essential for FGF21 activity.
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FGF21 binding promotes formation of a dimeric FGFR1c-KLB complex, activates tyrosine kinase domains and propagates signalling through ERK phosphorylation.
“FGF21 binding promotes the formation of a dimeric FGFR1c–KLB signalling complex, which activates the intracellular tyrosine kinase domains of FGFR1c and propagates signalling through phosphorylation by the kinase ERK46,53,58,59”
From Metabolic messengers: FGF21 (2021) · cites this paper as [53]
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 [53]
Endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is β-klotho.
“Importantly, since FGF receptors are ubiquitously expressed, endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is the coreceptor β-klotho (71, 99, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [99]
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 [99]
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BackgroundMuscle mitochondrial stress adaptation operates independently of endogenous FGF21 action
Ost, M., Coleman, V., Voigt, A., van Schothorst, E. M., Keipert, S., van der Stelt, I., Ringel, S., Graja, A., Ambrosi, T., Kipp, A. P., et al. (2016) · Molecular Metabolism · doi:10.1016/j.molmet.2015.11.002 · Cited by 75 · see citing works
Fibroblast growth factor-21 controls dietary protein intake in male mice
Larson, K. R., Chaffin, A. T.-B., Goodson, M. L., Fang, Y., & Ryan, K. K. (2019) · Endocrinology · doi:10.1210/en.2018-01056 · Cited by 68 · see citing works
Sex differences in the hormonal and metabolic response to dietary protein dilution
Larson, K. R., Russo, K. A., Fang, Y., Mohajerani, N., Goodson, M. L., & Ryan, K. K. (2017) · Endocrinology · doi:10.1210/en.2017-00331 · Cited by 66 · see citing works
FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPARα and PPARγ Agonists
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- Authors
- Ogawa, Y., Kurosu, H., Yamamoto, M., Nandi, A., Rosenblatt, K. P., Goetz, R., Eliseenkova, A. V., Mohammadi, M., & Kuro-o, M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- New York University (US)
- *Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390; and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-05
- Volume
- 104
- Issue
- 18
- Pages
- 7432-7437
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1855074
- OpenAlex
- W2130700195
- Cited by
- 617
- References
- 26
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 37 · 2023: 29 · 2022: 36 · 2021: 35 · 2020: 33 · 2019: 39 · 2018: 33 · 2017: 54 · 2016: 38 · 2015: 29 · 2014: 24 · 2013: 34 · 2012: 45
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- University of Texas Southwestern Medical Center
- Ted Nash Long Life Foundation
- Eisai
- National Institutes of Health
- National Institute on Aging (R01AG19712, R01AG25326, R01AG025326, R01AG019712)
- National Institute of Dental and Craniofacial Research (R01DE13686, R01DE013686)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- β-Klotho, FGF21, fibroblast growth factor receptor, FGF receptor 4, MAPK signaling, glucose uptake, adipocytes, white adipose tissue, preadipocyte differentiation, hormone signaling, cofactors
- MeSH terms
- Klotho Proteins, Animals, Cell Line, Fibroblast Growth Factors, Gene Expression Regulation, Humans, Membrane Proteins, Protein Binding, Signal Transduction, Receptors, Fibroblast Growth Factor, Adipocytes, Mice
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