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Role of insulin resistance on allergic airway inflammation in obese mice.

Grant number: 12/14225-1
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): December 01, 2012
Effective date (End): March 31, 2016
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal Investigator:Edson Antunes
Grantee:Marina Ciarallo Calixto
Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Obesity and asthma are prevalent and increasing desease, and both have significant impact on global public health. The increase in prevalence of asthma and obesity has led researchers to suggest that obesity may be an important factor in the development of asthma, or even worse a framework of pre-existing asthma. However, to date, few studies aimed to examining the mechanisms involved in the exacerbation of asthma in obese animals, and those that exist, most have only sought to assess bronchial hyperresponsiveness. There are about five years we initiated a study to standardized a model of obesity in C57BL6/J mice, by a high fat diet, for understanding the pathophysiological mechanisms present in the exacerbation of pulmonary inflammatory response allergic animals sensitized and challenged with ovalbumin (OVA). During this period, we observed that diet induced obese mice become insulin resistant and exhibit exacerbation of lung eosinophil infiltration upon challenge with ovalbumin (OVA), a phenomenon accompanied by marked eosinopoese. Another important finding was the observation of our group that treatment with anti-hyperglycemic, metformin, diminishes both insulin resistance such as eosinophilic inflammation in the lung of obese mice. Metformin also decreses the elevated levels of TNF-±, eotaxin and NOx, and expression of iNOS in lung tissue. Currently, it is well established that NO plays important modulatory role in the development of obesity and insulin resistance. Considering that NO is touted as the key mediator in asthmatic inflammation and that this mediator levels are elevated in bronchoalveolar lavage (BAL) obese mice, it becomes important to study whether the excessive production of NO is directly related to the development of insulin resistance in the lung of obese animals, which may take place by nitration and nitrosylation of proteins essential for glucose uptake. Thus, in this project we will: 1) To elucidate the importance of insulin resistance to pulmonary eosinophil recruitment in obese animals and challenged with OVA, with special attention to the expression of proteins involved in insulin signaling pathway such as p-IR, p-IRS- 1, p-AKT and GLUT4 in lung and isolated bronchus, 2) To assess whether the decrease in eosinophilic lung by metformin observed in obese animals is associated with changes in the expression of p-IR, p-IRS-1 and p-AKT in lung tissue and 3) To investigate the effect of anti-oxidant, resveratrol, on the allergic lung inflammation by analyzing the cellular profile in the BAL fluid and bone marrow, and the expression of p-AMPK, SIRT1 and PDE4 in the lung of allergic obese mice (this purpose assumes that reactive oxygen species and nitrogen have been implicated in asthma and obesity, and that resveratrol attenuates the development of insulin resistance in rodents fed a high fat diet, by activating p-AMPK and SIRT1 via PDE4).

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CALIXTO, MARINA CIARALLO; LINTOMEN, LETICIA; ANDRE, DIANA MAJOLI; LEIRIA, LUIZ OSORIO; FERREIRA, DANILO; LELLIS-SANTOS, CAMILO; ANHE, GABRIEL FORATO; BORDIN, SILVANA; LANDGRAF, RICHARDT GAMA; ANTUNES, EDSON. Metformin Attenuates the Exacerbation of the Allergic Eosinophilic Inflammation in High Fat-Diet-Induced Obesity in Mice. PLoS One, v. 8, n. 10, . (12/14225-1)

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