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Conference Paper: Fibroblast growth factor-21 promotes glucose uptake through activation of the serum response factor/ Ets-like protein-1 signaling cascade in Adipocytes
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TitleFibroblast growth factor-21 promotes glucose uptake through activation of the serum response factor/ Ets-like protein-1 signaling cascade in Adipocytes
 
AuthorsGe, X
Chen, C
Hui, X
Wang, Y
Lam, KSL
Xu, A
 
Issue Date2011
 
PublisherAmerican Diabetes Association (ADA).
 
CitationThe ‎71st Scientific Sessions of the American Diabetes Association (ADA 2011), San Diego, CA., 24-28 June 2011. [How to Cite?]
 
AbstractRESULTS: Fibroblast Growth Factor-21 (FGF-21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. Several previous studies indicated that FGF-21 induces glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipocytes. However, the molecular events underlying its actions in adipocyte remain poorly characterized. Here we investigated the signalling pathways that mediate FGF21-induced GLUT1 expression in vitro and in animals. Quantitative real-time PCR and luciferase reporter assay showed that FGF-21 induced GLUT1 expression through transcriptional activation. Suppression of the protein kinase ERK1/2 by its pharmacological inhibitor PD98059 abolished FGF21-induced glucose uptake and transactivation of the GLUT1 gene, indicating that FGF-21 transactivates GLUT1 through ERK1/2. The luciferase reporter assay demonstrated that truncation of -3174 bp to -3105 bp of the GLUT1 promoter, which contains two highly conserved Serum Response Element (SRE) and E-Twenty Six (ETS) binding motifs, dramatically decreased the promoter activity of the GLUT1 gene. Furthermore, mutations in either of these two core elements completely abolished the promoter activity of GLUT1. Chromatin immunoprecipitation (ChIP) assay demonstrated that the transcription factors Serum Response Factor (SRF) and Ets-like protein-1 (Elk-1), both of which are the downstream targets of ERK1/2, were recruited to the GLUT1 promoter upon FGF-21 stimulation. Explant studies on epididymal fats showed that FGF21-evoked phosphorylation of ERK/12, expression of GLUT1 and glucose uptake in high fat diet-induced obese mice were significantly attenuated compared to lean littermates, implying the presence of a FGF-21 resistant state in obese adipose tissue. In conclusion, FGF-21 induces GLUT1 expression through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcription of GLUT1 to enhance glucose uptake in adipocytes. The present findings highlight the potential of FGF-21 as a drug target for obesity-related metabolic diseases.
 
DescriptionCategory: Signal Transduction (Not Insulin Action): abstract no. 212-OR
 
DC FieldValue
dc.contributor.authorGe, X
 
dc.contributor.authorChen, C
 
dc.contributor.authorHui, X
 
dc.contributor.authorWang, Y
 
dc.contributor.authorLam, KSL
 
dc.contributor.authorXu, A
 
dc.date.accessioned2011-09-23T06:16:03Z
 
dc.date.available2011-09-23T06:16:03Z
 
dc.date.issued2011
 
dc.description.abstractRESULTS: Fibroblast Growth Factor-21 (FGF-21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. Several previous studies indicated that FGF-21 induces glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipocytes. However, the molecular events underlying its actions in adipocyte remain poorly characterized. Here we investigated the signalling pathways that mediate FGF21-induced GLUT1 expression in vitro and in animals. Quantitative real-time PCR and luciferase reporter assay showed that FGF-21 induced GLUT1 expression through transcriptional activation. Suppression of the protein kinase ERK1/2 by its pharmacological inhibitor PD98059 abolished FGF21-induced glucose uptake and transactivation of the GLUT1 gene, indicating that FGF-21 transactivates GLUT1 through ERK1/2. The luciferase reporter assay demonstrated that truncation of -3174 bp to -3105 bp of the GLUT1 promoter, which contains two highly conserved Serum Response Element (SRE) and E-Twenty Six (ETS) binding motifs, dramatically decreased the promoter activity of the GLUT1 gene. Furthermore, mutations in either of these two core elements completely abolished the promoter activity of GLUT1. Chromatin immunoprecipitation (ChIP) assay demonstrated that the transcription factors Serum Response Factor (SRF) and Ets-like protein-1 (Elk-1), both of which are the downstream targets of ERK1/2, were recruited to the GLUT1 promoter upon FGF-21 stimulation. Explant studies on epididymal fats showed that FGF21-evoked phosphorylation of ERK/12, expression of GLUT1 and glucose uptake in high fat diet-induced obese mice were significantly attenuated compared to lean littermates, implying the presence of a FGF-21 resistant state in obese adipose tissue. In conclusion, FGF-21 induces GLUT1 expression through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcription of GLUT1 to enhance glucose uptake in adipocytes. The present findings highlight the potential of FGF-21 as a drug target for obesity-related metabolic diseases.
 
dc.description.naturelink_to_OA_fulltext
 
dc.descriptionCategory: Signal Transduction (Not Insulin Action): abstract no. 212-OR
 
dc.identifier.citationThe ‎71st Scientific Sessions of the American Diabetes Association (ADA 2011), San Diego, CA., 24-28 June 2011. [How to Cite?]
 
dc.identifier.hkuros194045
 
dc.identifier.urihttp://hdl.handle.net/10722/140610
 
dc.languageeng
 
dc.publisherAmerican Diabetes Association (ADA).
 
dc.publisher.placeUnited States
 
dc.relation.ispartof71st ADA Scientific Sessions 2011
 
dc.titleFibroblast growth factor-21 promotes glucose uptake through activation of the serum response factor/ Ets-like protein-1 signaling cascade in Adipocytes
 
dc.typeConference_Paper
 
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<item><contributor.author>Ge, X</contributor.author>
<contributor.author>Chen, C</contributor.author>
<contributor.author>Hui, X</contributor.author>
<contributor.author>Wang, Y</contributor.author>
<contributor.author>Lam, KSL</contributor.author>
<contributor.author>Xu, A</contributor.author>
<date.accessioned>2011-09-23T06:16:03Z</date.accessioned>
<date.available>2011-09-23T06:16:03Z</date.available>
<date.issued>2011</date.issued>
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<description>Category: Signal Transduction (Not Insulin Action): abstract no. 212-OR</description>
<description.abstract>RESULTS: Fibroblast Growth Factor-21 (FGF-21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. Several previous studies indicated that FGF-21 induces glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipocytes. However, the molecular events underlying its actions in adipocyte remain poorly characterized. Here we investigated the signalling pathways that mediate FGF21-induced GLUT1 expression in vitro and in animals. Quantitative real-time PCR and luciferase reporter assay showed that FGF-21 induced GLUT1 expression through transcriptional activation. Suppression of the protein kinase ERK1/2 by its pharmacological inhibitor PD98059 abolished FGF21-induced glucose uptake and transactivation of the GLUT1 gene, indicating that FGF-21 transactivates GLUT1 through ERK1/2. The luciferase reporter assay demonstrated that truncation of -3174 bp to -3105 bp of the GLUT1 promoter, which contains two highly conserved Serum Response Element (SRE) and E-Twenty Six (ETS) binding motifs, dramatically decreased the promoter activity of the GLUT1 gene. Furthermore, mutations in either of these two core elements completely abolished the promoter activity of GLUT1. Chromatin immunoprecipitation (ChIP) assay demonstrated that the transcription factors Serum Response Factor (SRF) and Ets-like protein-1 (Elk-1), both of which are the downstream targets of ERK1/2, were recruited to the GLUT1 promoter upon FGF-21 stimulation. Explant studies on epididymal fats showed that FGF21-evoked phosphorylation of ERK/12, expression of GLUT1 and glucose uptake in high fat diet-induced obese mice were significantly attenuated compared to lean littermates, implying the presence of a FGF-21 resistant state in obese adipose tissue. In conclusion, FGF-21 induces GLUT1 expression through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcription of GLUT1 to enhance glucose uptake in adipocytes. The present findings highlight the potential of FGF-21 as a drug target for obesity-related metabolic diseases.</description.abstract>
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