Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice

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dc.contributor.authorCalixto, Marina Ciarallo
dc.contributor.authorLintomen, Leticia
dc.contributor.authorAndre, Diana Majoli
dc.contributor.authorLeiria, Luiz Osorio
dc.contributor.authorFerreira, Danilo
dc.contributor.authorLellis-Santos, Camilo
dc.contributor.authorAnhe, Gabriel Forato
dc.contributor.authorBordin, Silvana
dc.contributor.authorLandgraf, Richardt Gama [UNIFESP]
dc.contributor.authorAntunes, Edson
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T14:34:35Z
dc.date.available2016-01-24T14:34:35Z
dc.date.issued2013-10-24
dc.description.abstractA 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.en
dc.description.affiliationState Univ Campinas UNICAMP, Fac Med Sci, Dept Pharmacol, Campinas, SP, Brazil
dc.description.affiliationUniv São Paulo, Inst Biomed Sci, Dept Physiol & Biophys, São Paulo, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIDFAPESP: 2012/14225-1
dc.format.extent13
dc.identifierhttp://dx.doi.org/10.1371/journal.pone.0076786
dc.identifier.citationPlos One. San Francisco: Public Library Science, v. 8, n. 10, 13 p., 2013.
dc.identifier.doi10.1371/journal.pone.0076786
dc.identifier.fileWOS000326152300010.pdf
dc.identifier.issn1932-6203
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/36880
dc.identifier.wosWOS:000326152300010
dc.language.isoeng
dc.publisherPublic Library Science
dc.relation.ispartofPlos One
dc.rightsAcesso aberto
dc.titleMetformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Miceen
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