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Evaluation of intestinal microbiota and the mechanism of S-nitrosation in iNOS KO mice treated with high-fat diet

Grant number: 17/10179-9
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): September 01, 2017
Effective date (End): August 31, 2018
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Mario Jose Abdalla Saad
Grantee:Tamires Marques Zanotto
Supervisor abroad: Carl Ronald Kahn
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: Harvard University, Boston, United States  
Associated to the scholarship:16/07122-2 - Obesity and insulin resistance: iNOS effect on intestinal microbiota and endoplasmic reticulum stress in liver and adipose tissue of mice, BP.DD

Abstract

Obesity, a disease characterized by low-grade chronic inflammation in adipose tissue, results from the disturbance of the body's energy balance, induced by factors such as overnutrition and sedentary lifestyle, leading to weight gain and metabolic disorders. Several intracellular pathways are associated with Insulin Resistance (IR) occurrence and, among them, it's the iNOS enzyme, which is induced by pro-inflammatory cytokines during obesity. Many studies have demonstrated in obese mice, the iNOS overexpression imparing insulin signaling and action in peripheral tissues and that, in iNOS KO mice, there is a reversal of fasting hyperglycemia and hyperinsulinemia, improving IR. Since the mechanisms responsible for the emergence of obesity and insulin resistance have not been fully investigated yet, it is necessary to study the various conditions that may lead to these pathologies. Recently, studies have shown differences in the intestinal microbiota composition of obese individuals compared to lean individuals, with different proportions in the bacterial phyla. Beyond that, the iNOS expression was described as capable of changes in the intestinal tissue. This, highlights the importance of the gut microbiota study in iNOS knockout mice, for the better understanding of the mechanisms that lead to variations in this microenvironment, and if these variations can cause differences in insulin sensitivity. In this regard, the first aim of the study is to investigate the iNOS involvement in the intestinal microbiota composition, through the evaluation of metagenomic profile of iNOS KO mice trated with high-fat diet. Other relevant aspect is this enzyme involvement on the Endoplasmic Reticulum (ER) Stress mechanism, since there is an increase in iNOS expression and NO production in these situations. However, the mechanisms by which inactivation of iNOS protects against ER stress was not completely demonstrated. Given this, the second aim is to investigate the iNOS involvement on the s-nitrosation of the UPR key proteins (ATF6 and PERK). This study is of great importance for the better understanding of these processes, leading to the discovery of new therapeutic forms involving the iNOS pathway, modulating the ER stress and its associated diseases. (AU)

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