βKlotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism
Open accessAbstract
Fibroblast growth factor 21 (FGF21) is a fasting-induced hepatokine that has potent pharmacologic effects in mice, which include improving insulin sensitivity and blunting growth. The single-transmembrane protein βKlotho functions as a coreceptor for FGF21 in vitro. To determine if βKlotho is required for FGF21 action in vivo, we generated whole-body and adipose tissue-selective βKlotho-knockout mice. All of the effects of FGF21 on growth and metabolism were lost in whole-body βKlotho-knockout mice. Selective elimination of βKlotho in adipose tissue blocked the acute insulin-sensitizing effects of FGF21. Taken together, these data demonstrate that βKlotho is essential for FGF21 activity and that βKlotho in adipose tissue contributes to the beneficial metabolic actions of FGF21.
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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 [56]
The decrease in plasma glucose occurs primarily through increased peripheral glucose disposal, although decreases in hepatic glucose production have also been observed.
“This decrease in plasma glucose levels occurs primarily through increased peripheral glucose disposal41,56,65, although decreases in hepatic glucose production have also been observed66.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [56]
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 [27]
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 [27]
In wild-type lean mice, coinjection of FGF21 with insulin recapitulates the glucose-lowering effect.
“This effect of FGF21 can be recapitulated in wild-type lean mice through coinjection with insulin (11, 27), suggesting that FGF21 functions to directly enhance insulin sensitivity.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [27]
Acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production.
“The acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production (27, 142).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [27]
FGF21 stimulates glucose uptake in BAT in vivo.
“Multiple studies have demonstrated that FGF21 stimulates glucose uptake in BAT in vivo (11, 27, 86, 115).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [27]
Cellular FGF21 signaling is mediated by a receptor complex including FGFR1c and beta-Klotho (Klb), with Klb providing cellular specificity and FGFR driving intracellular signaling.
“Cellular FGF21 signaling is mediated by a receptor complex that includes a classic FGF receptor (FGFR1c) and a co-receptor known as beta-Klotho (Klb), with Klb functioning as the primary binding/targeting factor providing cellular specificity and FGFR functioning as the catalytic subunit that drives intracellular signaling”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [113]
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References 34 · Cited by 403
- Authors
- Ding, X., Boney-Montoya, J., Owen, B. M., Bookout, A. L., Coate, K. C., Mangelsdorf, D. J., & Kliewer, S. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mangelsdorf, David J.
- Kliewer, Steven A.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 16
- Issue
- 3
- Pages
- 387-393
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3447537
- OpenAlex
- W2064125892
- Cited by
- 403
- References
- 34
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 21 · 2023: 16 · 2022: 29 · 2021: 30 · 2020: 34 · 2019: 33 · 2018: 27 · 2017: 42 · 2016: 41 · 2015: 38 · 2014: 24 · 2013: 23 · 2012: 2
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (T32GM007062, GM007062, RL1GM084436)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-067158, U19 DK-62434, U19DK062434, R56DK089600, R01DK067158)
- National Center for Research Resources (P20RR20691, P20RR020691)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- β-Klotho, FGF21, adipose tissue, insulin sensitivity, growth regulation, metabolic effects, knockout mice
- MeSH terms
- Klotho Proteins, Adipose Tissue, Animals, Body Composition, Chromatography, Gel, Energy Metabolism, Fibroblast Growth Factors, Glucose Tolerance Test, Growth, Insulin Resistance, Membrane Proteins, Mice, Knockout, Mice
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