The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue

Andrew C. Adams; Chaofeng Yang; Tamer Coskun; Christine C. Cheng; Ruth E. Gimeno; Yongde Luo; Alexei Kharitonenkov

doi:10.1016/j.molmet.2012.08.007

The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue

Andrew C. Adams, Chaofeng Yang, Tamer Coskun, Christine C. Cheng, Ruth E. Gimeno, Yongde Luo, Alexei Kharitonenkov

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

Abstract

FGF21 is a multifunctional metabolic regulator. The co-factor ΒKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.

Original language	English (US)
Pages (from-to)	31-37
Number of pages	7
Journal	Molecular Metabolism
Volume	2
Issue number	1
DOIs	https://doi.org/10.1016/j.molmet.2012.08.007
State	Published - Feb 2013
Externally published	Yes

Keywords

Adipose tissue
FGF19
FGF21
FGFR1

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molmet.2012.08.007

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title = "The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue",

abstract = "FGF21 is a multifunctional metabolic regulator. The co-factor ΒKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.",

keywords = "Adipose tissue, FGF19, FGF21, FGFR1",

author = "Adams, {Andrew C.} and Chaofeng Yang and Tamer Coskun and Cheng, {Christine C.} and Gimeno, {Ruth E.} and Yongde Luo and Alexei Kharitonenkov",

note = "Funding Information: We thank Prof W McKeehan (Texas A&M Health Science Center, Houston, TX) for contributions to conceptual aspects of the study and provision of the FGFR1 lox/lox AP2 CRE mice. CY and YL were supported by grants from Eli Lilly , the Susan Komen Foundation and the John S. Dunn Foundation . ",

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doi = "10.1016/j.molmet.2012.08.007",

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AU - Adams, Andrew C.

AU - Yang, Chaofeng

AU - Coskun, Tamer

AU - Cheng, Christine C.

AU - Gimeno, Ruth E.

AU - Luo, Yongde

AU - Kharitonenkov, Alexei

N1 - Funding Information: We thank Prof W McKeehan (Texas A&M Health Science Center, Houston, TX) for contributions to conceptual aspects of the study and provision of the FGFR1 lox/lox AP2 CRE mice. CY and YL were supported by grants from Eli Lilly , the Susan Komen Foundation and the John S. Dunn Foundation .

PY - 2013/2

Y1 - 2013/2

N2 - FGF21 is a multifunctional metabolic regulator. The co-factor ΒKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.

AB - FGF21 is a multifunctional metabolic regulator. The co-factor ΒKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.

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The breadth of FGF21's metabolic actions are governed by FGFR1 in adipose tissue

Abstract

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