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.
Highlights
Obesity is strongly associated with metabolic syndrome, hypertension, dyslipidemia and hyperglycemic tendencies that are represented at the molecular level by insulin resistance (IR) [1]
This study shows that treatment of obese mice with the AMPK activator metformin suppressed IR and significantly reduced the OVA-induced eosinophil trafficking to the lung tissue, which was accompanied by reductions in the levels of eotaxin, TNF-α and NOx in bronchoalveolar lavage (BAL) fluid
acetyl CoA carboxylase (ACC) in the lung tissue of obese mice indicating that AMPK activation may be a good pharmacological strategy to control the asthma exacerbation in obese individuals
Summary
Obesity is strongly associated with metabolic syndrome, hypertension, dyslipidemia and hyperglycemic tendencies that are represented at the molecular level by insulin resistance (IR) [1]. Obesity and weight gain are considered risk factors for asthma exacerbations [2]. Studies show that IR accounts for most of the obesity-associated asthma risk in children and adults [2,6]. Airway hyperresponsiveness is enhanced in genetically obese mice [8]. Ovalbumin (OVA) challenge in previously sensitized ob/ob mice (that are obese as a result of a genetic leptin deficiency) aggravates the pulmonary resistance [9] and eosinophilic inflammation [10]. High-fat diet-induced obesity was recently shown to exacerbate the lung eosinophilic inflammation through enhanced eosinophil trafficking from bone marrow to lung tissues, and delayed their transit through the airway epithelium into the airway lumen [11]
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