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Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration
Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene de...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686718/ https://www.ncbi.nlm.nih.gov/pubmed/34074713 http://dx.doi.org/10.1124/jpet.121.000514 |
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author | Girer, Nathaniel G. Rontoyanni, Victoria G. Joshi, Aditya Patrikeev, Igor Murton, Andrew J. Porter, Craig Motamedi, Massoud Elferink, Cornelis J. |
author_facet | Girer, Nathaniel G. Rontoyanni, Victoria G. Joshi, Aditya Patrikeev, Igor Murton, Andrew J. Porter, Craig Motamedi, Massoud Elferink, Cornelis J. |
author_sort | Girer, Nathaniel G. |
collection | PubMed |
description | Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animal models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least 2 weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within 2 weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1–dependent thermogenesis in brown fat and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease. SIGNIFICANCE STATEMENT: This study presents a valuable method for nonviral gene delivery in mice that improves upon existing techniques. The data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease and will likely enhance in vivo studies characterizing liver protein function. |
format | Online Article Text |
id | pubmed-8686718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-86867182021-12-21 Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration Girer, Nathaniel G. Rontoyanni, Victoria G. Joshi, Aditya Patrikeev, Igor Murton, Andrew J. Porter, Craig Motamedi, Massoud Elferink, Cornelis J. J Pharmacol Exp Ther Endocrine and Diabetes Viral-mediated in vivo gene delivery methods currently dominate among therapeutic strategies within the clinical and experimental settings, albeit with well documented limitations arising from immunologic constraints. In this study, we demonstrate the utility of nonviral hepatotropic in vivo gene delivery of unpackaged expression constructs, including one encoding fibroblast growth factor 21 (FGF21). FGF21 is an important hepatokine whose expression positively correlates with therapeutic outcomes across various animal models of obesity. Our data demonstrate that FGF21 expression can be restored into the livers of immunocompetent FGF21 knockout mice for at least 2 weeks after a single injection with an FGF21 expression plasmid. In wild-type C57BL6/J mice, in vivo transfection with an FGF21-expressing plasmid induced weight loss, decreased adiposity, and activated thermogenesis in white fat within 2 weeks. Furthermore, in vivo FGF21 gene delivery protected C57BL6/J mice against diet-induced obesity by decreasing adiposity and increasing uncoupling protein 1–dependent thermogenesis in brown fat and by boosting respiratory capacity in subcutaneous and perigonadal white fat. Together, the data illustrate a facile and effective methodology for delivering prolonged protein expression specifically to the liver. We contend that this method will find utility in basic science research as a practical means to enhance in vivo studies characterizing liver protein function. We further believe our data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease. SIGNIFICANCE STATEMENT: This study presents a valuable method for nonviral gene delivery in mice that improves upon existing techniques. The data provide a rationale for further exploring the potential clinical utility of nonviral gene therapy in mouse models of disease and will likely enhance in vivo studies characterizing liver protein function. American Society for Biochemistry and Molecular Biology 2021-08 2021-08 /pmc/articles/PMC8686718/ /pubmed/34074713 http://dx.doi.org/10.1124/jpet.121.000514 Text en Copyright © 2021 by The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the CC BY Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Endocrine and Diabetes Girer, Nathaniel G. Rontoyanni, Victoria G. Joshi, Aditya Patrikeev, Igor Murton, Andrew J. Porter, Craig Motamedi, Massoud Elferink, Cornelis J. Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration |
title | Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration |
title_full | Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration |
title_fullStr | Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration |
title_full_unstemmed | Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration |
title_short | Liver-Specific Nonviral Gene Delivery of Fibroblast Growth Factor 21 Protein Expression in Mice Regulates Body Mass and White/Brown Fat Respiration |
title_sort | liver-specific nonviral gene delivery of fibroblast growth factor 21 protein expression in mice regulates body mass and white/brown fat respiration |
topic | Endocrine and Diabetes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8686718/ https://www.ncbi.nlm.nih.gov/pubmed/34074713 http://dx.doi.org/10.1124/jpet.121.000514 |
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