title: Metformin attenuates the exacerbation of the allergic eosinophilic inflammation in high fat-diet-induced obesity in mice.
abstract: 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-α 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-κB 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-α mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. In conclusion, metformin inhibits the TNF-α-induced inflammatory signaling and NF-κB-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.
authors.affiliation: Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: Marina Ciarallo
authors.initials: MC
authors.lastname: Calixto
authors.forename: Letícia
authors.initials: L
authors.lastname: Lintomen
authors.forename: Diana Majoli
authors.initials: DM
authors.lastname: André
authors.forename: Luiz Osório
authors.initials: LO
authors.lastname: Leiria
authors.forename: Danilo
authors.initials: D
authors.lastname: Ferreira
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.forename: Gabriel Forato
authors.initials: GF
authors.lastname: Anhê
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
authors.forename: Richardt Gama
authors.initials: RG
authors.lastname: Landgraf
authors.forename: Edson
authors.initials: E
authors.lastname: Antunes
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001249:Asthma / Q000150:complications*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D059305:Diet, High-Fat / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D007333:Insulin Resistance; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000209:etiology / Q000378:metabolism; D010047:Ovalbumin / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D007004:Hypoglycemic Agents; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D010047:Ovalbumin; D008687:Metformin; D052247:Nitric Oxide Synthase Type II; D055372:AMP-Activated Protein Kinases; C004479:pimagedine