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Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer

FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation (1,2). Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis...

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Autores principales: Suh, Jae Myoung, Jonker, Johan W., Ahmadian, Maryam, Goetz, Regina, Lackey, Denise, Osborn, Olivia, Huang, Zifeng, Liu, Weilin, Yoshihara, Eiji, van Dijk, Theo, Havinga, Rick, Fan, Weiwei, Yin, Yun-Qiang, Yu, Ruth T., Liddle, Christopher, Atkins, Annette R., Olefsky, Jerrold M., Mohammadi, Moosa, Downes, Michael, Evans, Ronald M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184286/
https://www.ncbi.nlm.nih.gov/pubmed/25043058
http://dx.doi.org/10.1038/nature13540
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author Suh, Jae Myoung
Jonker, Johan W.
Ahmadian, Maryam
Goetz, Regina
Lackey, Denise
Osborn, Olivia
Huang, Zifeng
Liu, Weilin
Yoshihara, Eiji
van Dijk, Theo
Havinga, Rick
Fan, Weiwei
Yin, Yun-Qiang
Yu, Ruth T.
Liddle, Christopher
Atkins, Annette R.
Olefsky, Jerrold M.
Mohammadi, Moosa
Downes, Michael
Evans, Ronald M.
author_facet Suh, Jae Myoung
Jonker, Johan W.
Ahmadian, Maryam
Goetz, Regina
Lackey, Denise
Osborn, Olivia
Huang, Zifeng
Liu, Weilin
Yoshihara, Eiji
van Dijk, Theo
Havinga, Rick
Fan, Weiwei
Yin, Yun-Qiang
Yu, Ruth T.
Liddle, Christopher
Atkins, Annette R.
Olefsky, Jerrold M.
Mohammadi, Moosa
Downes, Michael
Evans, Ronald M.
author_sort Suh, Jae Myoung
collection PubMed
description FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation (1,2). Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis (3,4). Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice that is dose-dependent, but does not lead to hypoglycemia. Chronic pharmacological rFGF1 treatment increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin sensitizing therapies. Furthermore, we demonstrate that the glucose lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 (FGFR1) signaling. In summary, we have uncovered an unexpected, neomorphic insulin sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for treatment of insulin resistance and type 2 diabetes.
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spelling pubmed-41842862015-03-18 Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer Suh, Jae Myoung Jonker, Johan W. Ahmadian, Maryam Goetz, Regina Lackey, Denise Osborn, Olivia Huang, Zifeng Liu, Weilin Yoshihara, Eiji van Dijk, Theo Havinga, Rick Fan, Weiwei Yin, Yun-Qiang Yu, Ruth T. Liddle, Christopher Atkins, Annette R. Olefsky, Jerrold M. Mohammadi, Moosa Downes, Michael Evans, Ronald M. Nature Article FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation (1,2). Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis (3,4). Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice that is dose-dependent, but does not lead to hypoglycemia. Chronic pharmacological rFGF1 treatment increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin sensitizing therapies. Furthermore, we demonstrate that the glucose lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 (FGFR1) signaling. In summary, we have uncovered an unexpected, neomorphic insulin sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for treatment of insulin resistance and type 2 diabetes. 2014-07-16 2014-09-18 /pmc/articles/PMC4184286/ /pubmed/25043058 http://dx.doi.org/10.1038/nature13540 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Suh, Jae Myoung
Jonker, Johan W.
Ahmadian, Maryam
Goetz, Regina
Lackey, Denise
Osborn, Olivia
Huang, Zifeng
Liu, Weilin
Yoshihara, Eiji
van Dijk, Theo
Havinga, Rick
Fan, Weiwei
Yin, Yun-Qiang
Yu, Ruth T.
Liddle, Christopher
Atkins, Annette R.
Olefsky, Jerrold M.
Mohammadi, Moosa
Downes, Michael
Evans, Ronald M.
Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
title Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
title_full Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
title_fullStr Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
title_full_unstemmed Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
title_short Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer
title_sort endocrinization of fgf1 produces a neomorphic and potent insulin sensitizer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184286/
https://www.ncbi.nlm.nih.gov/pubmed/25043058
http://dx.doi.org/10.1038/nature13540
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