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.

Obesity and Asthma in Children: Current and Future Therapeutic Options

“…However, in a chronic asthma model utilizing a different trigger (ovalbumin and fungal-associated allergenic protease), metformin reduced several asthma-related processes including eosinophilic and neutrophilic lung inflammation, peribronchial inflammatory cell infiltration, IgE responses, airway smooth muscle thickness, remodeling-related growth factor expression and airway oxidative stress [110]. In a separate study, metformin also eliminated the normal elevations seen in eotaxin, TNF-alpha, NOx and iNOS expression following murine ovalbumin sensitization and challenge[111]. Shore and colleagues in a study of human airway smooth muscle showed that thiazolidinediones (and possibly metformin) inhibit the production and release of several asthmagenic inflammatory mediators from airway smooth muscle possibly through mechanisms unrelated to AMPK activation [112].…”

Obesity and asthma: beyond TH2 inflammation

“…Notwithstanding, a possible potentiating effect of M1-released chemokines towards T H 2 inflammation in the lungs from obese mice must be considered. It was reported in a recent paper that long-term treatment with metformin in high-fat fed ovalbumin-challenged mice was able to reduce pulmonary eosinophilia by decreasing nitric oxide metabolite (NOx) production as a consequence of inhibition of lung NFkB p65-binding to the iNOS promoter region, which fails to be activated by TNF-α [98]. These data shed light on the possibility of a cross-talk between M1 macrophage-released TNF-α and T H 2-dependent inflammation, which may take place in obesity conditions.…”

Metformin use and asthma: Further investigations

“…This study supplements the possible mechanistic role of metformin in activating 5-adenosine monophosphate-activated protein kinase (AMPK), which is shown to attenuate allergic eosinophilic airway inflammation, 2 to inhibit TNF-α-induced inflammatory signalling 3 and to decrease oxidative stress, 4 thus providing evidence for possible beneficial role of metformin in asthma patients.…”