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1. modulation of double-stranded RNA-Activated protein kinase in insulin sensitive tissues of obese humans. 2. acute exercise induces a phenotypic switch in adipose tissue macrophage polarization in diet-induced obese rats. 3. influence of gut Microb.

Grant number: 14/01976-4
Support type:Regular Research Grants - Publications - Scientific article
Duration: March 01, 2014 - August 31, 2014
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Mario Jose Abdalla Saad
Grantee:Mario Jose Abdalla Saad
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

1. The double-stranded RNA-dependent protein kinase (PKR) was recently implicated inregulating molecular integration of nutrient- and pathogen-sensing pathways in obese mice. However, itsmodulation in human tissues in situations of insulin resistance has not been investigated. The present study was performed to first determine the tissue expression and phosphorylation levels of PKR in the liver, muscle, and adipose tissue in obese humans, and also the modulation of this protein in the adiposetissue of obese patients after bariatric surgery.Design and Methods: Eleven obese subjects who were scheduled to undergo Roux-en-Y Gastric BypassProcedure participated in this study. Nine apparently healthy lean subjects as a control group were also included. Our data show that PKR is activated in liver, muscle, and adipose tissue of obese humans and, after bariatric surgery, there is a clear reduction in PKR activation accompanied by a decrease in protein kinase-like endoplasmic reticulum kinase, c-Jun N-terminal kinase, inhibitor of kappa b kinase, and insulin receptor substrate-1 serine 312 phosphorylation in subcutaneous adipose tissue from these patients.Thus, it is proposed that PKR is an important mediator of obesity-induced insulin resistance and a potential target for the therapy.2. It has become clear that exercise may be a useful therapy in the insulin resistance treatment, as it has anti-inflammatory effects and improves insulin sensitivity. However, it remains uncertain whether exercise affects the adipocytes or infiltrated macrophages. Thus, the aim was to investigate the effects of acute exercise on the inflammatory status and insulin signaling of the white adipose tissue (WAT) fractions (stromal-vascular fraction [SVF] and adipocytes).The effect of acute swimming exercise was investigated on insulin sensitivity,insulin signaling, inflammatory pathways in the WAT fractions of high-fat fed Wistar rats. Additionally, macrophage infiltration and polarization were analyzed in the WAT.Results: Acute exercise can improve insulin signaling in WAT fractions, along with a phenotypic switch from M1- to M2-macrophages in obese rats, as indicated by a marked increase in macrophage galactose-type C-type lectin 1-positive cells in WAT was observed. Additionally, exercise promoted a reduction in circulating levels of lipopolysaccharide, and toll-like receptor 4 activity along with TNF-alpha, IL-1-beta and MCP-1 mRNA levels in WAT fractions.These data suggest that acute exercise improves insulin signaling in the WAT, at least in part by inducing macrophage polarization toward the M2-state.3. Obesity is the main condition that is correlated with the appearance of insulin resistance, which is the major link among itscomorbidities, such as type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases, and several types of cancer. Obesity affects a large number of individuals worldwide; it degrades human health and quality of life. Here, we review the role of the gut microbiota in the pathophysiology of obesity and type 2 diabetes, which is promoted by a bacterial diversity shift mediated by overnutrition. Whole bacteria, their products, and metabolites undergo increased translocation through the gut epithelium to the circulation due to degraded tight junctions and the consequent increase in intestinal permeability that culminates in inflammation and insulin resistance. Several strategies focusing on modulation of the gut microbiota (antibiotics, probiotics, and prebiotics) are being experimentally employed in metabolic derangement in order to reduce intestinal permeability, increase theproduction of short chain fatty acids and anorectic gut hormones, and promote insulin sensitivity to counteract the inflammatorystatus and insulin resistance found in obese individuals. (AU)