Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice
Autor(a) principal: | |
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Data de Publicação: | 2013 |
Outros Autores: | , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | http://repositorio.unifesp.br/handle/11600/36880 http://dx.doi.org/10.1371/journal.pone.0076786 |
Resumo: | A positive relationship between obesity and asthma has been well documented. the AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. the cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. in obese mice, greater levels of eotaxin, TNF-alpha and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. in addition, metformin nearly abrogated the binding of NF-kappa B subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. in separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-alpha mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. in conclusion, metformin inhibits the TNF-alpha-induced inflammatory signaling and NF-kappa B-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals. |
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Calixto, Marina CiaralloLintomen, LeticiaAndre, Diana MajoliLeiria, Luiz OsorioFerreira, DaniloLellis-Santos, CamiloAnhe, Gabriel ForatoBordin, SilvanaLandgraf, Richardt Gama [UNIFESP]Antunes, EdsonUniversidade Estadual de Campinas (UNICAMP)Universidade de São Paulo (USP)Universidade Federal de São Paulo (UNIFESP)2016-01-24T14:34:35Z2016-01-24T14:34:35Z2013-10-24Plos One. San Francisco: Public Library Science, v. 8, n. 10, 13 p., 2013.1932-6203http://repositorio.unifesp.br/handle/11600/36880http://dx.doi.org/10.1371/journal.pone.0076786WOS000326152300010.pdf10.1371/journal.pone.0076786WOS:000326152300010A positive relationship between obesity and asthma has been well documented. the AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. the cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. in obese mice, greater levels of eotaxin, TNF-alpha and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. in addition, metformin nearly abrogated the binding of NF-kappa B subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. in separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-alpha mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. in conclusion, metformin inhibits the TNF-alpha-induced inflammatory signaling and NF-kappa B-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)State Univ Campinas UNICAMP, Fac Med Sci, Dept Pharmacol, Campinas, SP, BrazilUniv São Paulo, Inst Biomed Sci, Dept Physiol & Biophys, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, BrazilFAPESP: 2012/14225-1Web of Science13engPublic Library SciencePlos OneMetformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Miceinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESPORIGINALWOS000326152300010.pdfapplication/pdf1977541${dspace.ui.url}/bitstream/11600/36880/1/WOS000326152300010.pdf04a71ac2451148a356b17e656bf8cad9MD51open accessTEXTWOS000326152300010.pdf.txtWOS000326152300010.pdf.txtExtracted texttext/plain54280${dspace.ui.url}/bitstream/11600/36880/2/WOS000326152300010.pdf.txt6e2bc24f131eaec2f0561b641cab33b1MD52open access11600/368802023-01-12 22:12:02.389open accessoai:repositorio.unifesp.br:11600/36880Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-01-13T01:12:02Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
title |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
spellingShingle |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice Calixto, Marina Ciarallo |
title_short |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
title_full |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
title_fullStr |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
title_full_unstemmed |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
title_sort |
Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice |
author |
Calixto, Marina Ciarallo |
author_facet |
Calixto, Marina Ciarallo Lintomen, Leticia Andre, Diana Majoli Leiria, Luiz Osorio Ferreira, Danilo Lellis-Santos, Camilo Anhe, Gabriel Forato Bordin, Silvana Landgraf, Richardt Gama [UNIFESP] Antunes, Edson |
author_role |
author |
author2 |
Lintomen, Leticia Andre, Diana Majoli Leiria, Luiz Osorio Ferreira, Danilo Lellis-Santos, Camilo Anhe, Gabriel Forato Bordin, Silvana Landgraf, Richardt Gama [UNIFESP] Antunes, Edson |
author2_role |
author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade Estadual de Campinas (UNICAMP) Universidade de São Paulo (USP) Universidade Federal de São Paulo (UNIFESP) |
dc.contributor.author.fl_str_mv |
Calixto, Marina Ciarallo Lintomen, Leticia Andre, Diana Majoli Leiria, Luiz Osorio Ferreira, Danilo Lellis-Santos, Camilo Anhe, Gabriel Forato Bordin, Silvana Landgraf, Richardt Gama [UNIFESP] Antunes, Edson |
description |
A positive relationship between obesity and asthma has been well documented. the AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. the cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. in obese mice, greater levels of eotaxin, TNF-alpha and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. in addition, metformin nearly abrogated the binding of NF-kappa B subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. in separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-alpha mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. in conclusion, metformin inhibits the TNF-alpha-induced inflammatory signaling and NF-kappa B-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals. |
publishDate |
2013 |
dc.date.issued.fl_str_mv |
2013-10-24 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:34:35Z |
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2016-01-24T14:34:35Z |
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article |
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dc.identifier.citation.fl_str_mv |
Plos One. San Francisco: Public Library Science, v. 8, n. 10, 13 p., 2013. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/36880 http://dx.doi.org/10.1371/journal.pone.0076786 |
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1932-6203 |
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WOS000326152300010.pdf |
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10.1371/journal.pone.0076786 |
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Plos One. San Francisco: Public Library Science, v. 8, n. 10, 13 p., 2013. 1932-6203 WOS000326152300010.pdf 10.1371/journal.pone.0076786 WOS:000326152300010 |
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