Evaluation of the role of dsRNA-dependent protein kinase (PKR) in the pathogenesis of insulin resistance and intestinal permeability in obesity.

• Grant number: 13/24026-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): April 01, 2014
• Effective date (End): September 30, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Mario Jose Abdalla Saad
• Grantee: Rodrigo Miguel Marin
• Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID

Abstract

The pathophysiology of insulin resistance in obesity is closely related to a low-grade chronic inflammation, but the mecanisms involved are not well understood. It is currently accepted that pro-inflammatory factors produced by the adipose tissue and the high levels of circulating fatty acids affect the transduction of insulin signaling in the peripheral tissues (e.g. liver and skeletal muscle) and in the central nervous system (hypothalamus). Also, numerous studies have implicated the intestinal tract and its microbiota as important precursors and mediators of systemic inflammation in the context of obesity. The exact mechanism by which the intestinal microbiota and inflammation contribute to the metabolic alterations associated with obesity, is still unclear. In this sense, it has been suggested that gram-negative bacteria-derived LPS induces changes in the intestinal permeability by disrupting Tight Junctions (TJ) structures, which in turn facilitates the access of this toxin to the systemic circulation. Recent studies shown that the dsRNA -dependent protein kinase (PKR) is a key component of the pro- inflammatory signaling involved in the mechanism of insulin resistance in obesity.The PKR was initially described as a mediator of the antiviral and antiproliferative activity of interferons . It is also known that its activity is modulated by different elements , such as growth factors , cytokines and pro-inflammatory stimuli (as the LPS ) and oxidative stress. Furthermore, there are experimental data that this protein interacts directly with the critical elements of insulin signaling pathway that regulates , in turn , the action of this hormone and metabolism. Based on the hypothesis that the PKR could act either directly on the disruption of intestinal TJ, due to its effect of inhibiting synthesis and induction of protein degradation , and on the chronic inflammation, this intracellular kinase has characteristics that make it a primary key component in the pathophysiology of insulin resistance in obesity conditions. However , there are no descriptions in the scientific literature of the role of PKR on the genesis of intestinal permeability changes and insulin resistance in obese individuals. Therefore, this project aims to assess the role of PKR in early induction of changes in the gut permeability of diet-induced obesity animals, shedding light on a new key molecular mechanism in the genesis and maintenance of insulin resistance in obesity.