Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB

Ecole Normale Supérieure de Lyon, France
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e33870. DOI: 10.1371/journal.pone.0033870
Source: PubMed

ABSTRACT Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear.
We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding, and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is an indispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1. Although FGF19 can predominantly activate the responses of the liver and to a less extent the adipose tissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolic and endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted by the ablation of KLB or FGFR1.
Our results indicate that unlike FGF19, FGF21 is unable to bind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiological concentration less likely to directly and significantly target the liver where FGFR4-KLB predominantly resides. However, both FGF21 and FGF19 have the potential to activate responses of primarily the adipose tissue where FGFR1-KLB resides.

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Available from: Chengliu Jin, Sep 28, 2015
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    • "In contrast to b-klotho, our study indicates that ER stress resulted in downregulation of FGFR3 and this effect was selective among FGFR family members. Although FGF21 shows high binding affinity to FGFR1 compared to other FGFR isoforms [35], it has been reported that FGF21 can also activate other FGFR isotypes including FGFR3 [34]. Down-regulation of FGFR3 by ER stress may contribute to impairment of FGF21 signaling in liver. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) plays critical roles in regulating glucose and lipid metabolism. β-Klotho is the co-receptor for mediating FGF21 signaling, and the mRNA levels of this receptor are increased in the liver of human subjects with obesity. However, the molecular mechanisms underlying the regulation of β-klotho expression remain poorly defined. Here, we report that elevation of β-klotho protein expression in diet-induced obese mice and human patients is associated with increased endoplasmic reticulum (ER) stress. In vivo study indicates that administration of the ER stressor tunicamycin in mice led to increased expression of β-klotho in the liver. In addition, we show that ER stress is sufficient to potentiate FGF21 signaling in HepG2 cell and ATF4 signaling pathway is essential for mediating the effect of ER stress on β-klotho expression. These findings demonstrate a link of ER stress with up-regulation of hepatic β-klotho expression and the molecular mechanism underlying ER stress-regulated FGF21 signaling. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 459(2). DOI:10.1016/j.bbrc.2015.02.104 · 2.30 Impact Factor
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    • "While FGF21 appeared to function via a classical FGFR-mediated mechanism, namely phosphorylation of FRS2 and subsequent activation of the MAPK signaling cascade, a mystery remained as to how FGF21 was able to activate FGFR since it was not able to bind the receptor directly. While it was proposed that FGF21 may require an adipocyte specific co-factor [8], it took several years and various approaches to finally identify the transmembrane protein βKlotho (KLB) as the necessary co-receptor able to permit FGF21 mediated activation of FGFRs in vitro [22–25] and promote FGF21 action in vivo [26–28]. "
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    ABSTRACT: Since the discovery of insulin in 1921, protein therapeutics have become vital tools in the treatment of diabetes mellitus. This heritage has been extended with the comparatively recent introduction of recombinant and re-engineered insulins, in addition to the advent of GLP1 agonists. FGF21 represents an example of a novel experimental protein therapy which is able to induce favorable metabolic effects in various species ranging from rodents to man. The aim of this review is to communicate the story of the FGF21 drug discovery path from identification in a functional in vitro screen, to the eventual evaluation of its utility in patients. Given that the development of FGF21 advanced hand-in-hand with rapidly evolving scientific research around this target, we have also attempted to describe our view of recent developments regarding the mechanistic understanding of FGF21 biology.
    Molecular Metabolism 06/2014; 3(3):221-229. DOI:10.1016/j.molmet.2013.12.003
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    • "Importantly, βKlotho [signalling co-factor functioning as a cell surface adaptor molecule binding to C-terminus of FGF21 component of FGF21/FGFR1 signalling complex] [39] has been proposed to modulate actions of FGF21 [40]. Moreover, studies have suggested decreased hepatic/adipose tissue expression levels of βKlotho in human obesity and DIO rodents resulting in decreased FGF21 signalling in target organs [12], [41]. Hence, given our novel observation of βKlotho in the heart and a significant decrease in cardiac gene and protein expression levels of βKlotho in obese rat hearts, may account for the ‘FGF21 resistance’ observed in our ex vivo experiments, which in turn disrupts FGFR1-FGF21-βKlotho signalling. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia.
    PLoS ONE 02/2014; 9(2):e87102. DOI:10.1371/journal.pone.0087102 · 3.23 Impact Factor
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