Modulation of inflammation and insulin resistance by omega-3 fatty acids and palmitoleate

Abstract

In despite of the fact that there are several studies showing the effects of fatty acids (FAs) on systemic metabolism and the consensus that high fat content in the diet is associated with insulin resistance and metabolic syndrome, the knowledge about omega-3 and omega-7 FAs related to inflammatory processes, insulin resistance, and, if there are additive or synergistic effects with regular physical exercise, is still incipient. The aim of this project is to investigate the effect of supplementation with omega-3 (fish oil) and omega-7 (macadamia oil) FAs, associated or not with regular physical activity, on inflammation and insulin resistance induced by high-fat diet. The following mice strains will be used: (1) C57BL/6, (2) Swiss, (3) knockout for TNF-alfa receptor (TNF-R1 -/-), (4) knockout for TLR-4 (TLR-4 -/-), (5) C3H/HeJ, (6) knockout for gp91phox (gp91phox -/-) and (7) transgenic mice that over express fat-1 gene (fat-1 +/+). Leukocytes (macrophages and neutrophils), skeletal muscle, adipose tissue and liver will be investigated. Mice will receive a balanced diet, supplemented or not with FAs during 12 weeks (weeks 0 to 12). In the weeks 5 to 12, a group of mice will continue receiving balanced diet and another group will receive high-fat diet. Trained mice will be submitted to treadmill exercise from week 0 to 12. At the end of the treatment, the following assessments will be perform: insulin sensitivity, inflammatory markers, glucose and FA metabolism, signaling, mitochondrial function, generation of reactive oxygen species (ROS), leukocyte function (cytokine production and phagocytosis), proteomic analysis and expression of genes related to glucose and FAs metabolism (GLUT-2, GLUT-4, FABPs, SCD-1, CPT1, CPT2, phosphoenolpyruvate carboxykinase, phosphofructokinase, citrate synthase), insulin signaling (insulin receptor, IRS-1 , IRS-2, Akt, GSK-3, MAPKs), inflammation (TNF-alfa JNK, NFºB, IL-6, IL-10, IL-1ra, ROS generation (MnSOD, CuZnSOD, catalase), and other genes also related to inflammation and obesity (PAI-1, leptin, resistin, adiponectin, MCP-1, PPARs, PGC-1alfa). A better understanding of the mechanisms involved in the action of FAs, associated or not with regular physical activity, will have direct impact on the elucidation of the issues related to obesity and associated conditions, as well as the development of new therapies that target intracellular pathways involved in inflammation. (AU)