Obesity and type 2 diabetes are conditions characterized by a state of chronic, low-grade inflammation, due largely to an increase in adipose tissue inflammation brought about by infiltrating macrophages. Drugs such as thiazolidinediones (TZDs) improve insulin sensitivity via activation of PPAR-gamma, and there is much evidence that PPAR3 agonists also have anti-inflammatory properties. In addition to their beneficial effects on serum lipids and heart disease, fish oils (I-3 fatty acids) activate PPAR3 and demonstrate anti-inflammatory properties. This is a translational research study intended to examine the mechanism for many of the beneficial effects of fish oils on metabolic syndrome in humans. We plan to treat insulin resistant subjects with fish oils and the following hypotheses. Hypothesis 1. The treatment of insulin resistant subjects with fish oils will reduce adipose tissue inflammation. We plan to examine the circulating levels of cytokines, as well as the levels of cytokines and macrophages in adipose tissue biopsies of subjects who are treated with 4 g/day of I-3 fatty acids for 12 weeks. We will determine whether there is evidence of macrophage apoptosis in adipose tissue, and we will determine whether I-3 fatty acids increases the level or secretion of adiponectin. Hypothesis 2. Anti-inflammatory effects of fish oils are mediated by activation of PPAR3 and/or by changes in membrane composition that affect signal transduction functions. Adipose tissue and macrophages will be treated in vitro with fish oils in the presence and absence of a PPAR3 inhibitor, and we will measure PPAR3 responses, such as the secretion of HMW adiponectin and macrophage apoptosis. In addition, we will determine whether I-3 fatty acids induce changes in recruitment of inflammatory receptors, such as toll-like receptor 4 (TLR4) and TNF1 Receptor 1 (TNFR1) to membrane rafts. Hypothesis 3. Fish oils improve peripheral insulin sensitivity through a reduction in intramyocellular lipid, and an improvement in muscle insulin signal transduction. Before and after treatment with fish oils, insulin sensitivity will be measured, along with intramyocellular lipid and genes or proteins involved in insulin action and muscle lipid oxidation. Project Narrative: The incidence of obesity, metabolic syndrome, and diabetes is rising in epidemic proportions in the Western world, and the resultant heart disease will likely create a generation who will not live as long as their parents. Fish oils have proven health benefits on coronary risk factors, and this study aims to develop evidence for additional properties of fish oils that will greatly extend their use to subjects with insulin resistance and metabolic syndrome.
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