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. ? ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Staten, Myrlene A
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University of Arkansas for Medical Sciences
Internal Medicine/Medicine
Schools of Medicine
Little Rock
United States
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Lawler, Helen M; Underkofler, Chantal M; Kern, Philip A et al. (2016) Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects. J Clin Endocrinol Metab 101:1422-8
Spencer, Michael; Yang, Lin; Adu, Akosua et al. (2014) Pioglitazone treatment reduces adipose tissue inflammation through reduction of mast cell and macrophage number and by improving vascularity. PLoS One 9:e102190
Kern, Philip A; Finlin, Brian S; Zhu, Beibei et al. (2014) The effects of temperature and seasons on subcutaneous white adipose tissue in humans: evidence for thermogenic gene induction. J Clin Endocrinol Metab 99:E2772-9
Finlin, Brian S; Zhu, Beibei; Starnes, Catherine P et al. (2013) Regulation of thrombospondin-1 expression in alternatively activated macrophages and adipocytes: role of cellular cross talk and omega-3 fatty acids. J Nutr Biochem 24:1571-9
Spencer, Michael; Finlin, Brian S; Unal, Resat et al. (2013) Omega-3 fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Diabetes 62:1709-17
Finlin, Brian S; Varma, Vijayalakshmi; Nolen, Greg T et al. (2012) DHA reduces the atrophy-associated Fn14 protein in differentiated myotubes during coculture with macrophages. J Nutr Biochem 23:885-91
Ranganathan, Gouri; Unal, Resat; Pokrovskaya, Irina D et al. (2012) The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation. Atherosclerosis 221:143-7
Finlin, Brian S; Bodles-Brakhop, Angela M; Yao-Borengasser, Aiwei et al. (2012) Regulation of small ubiquitin-like modifier-1, nuclear receptor coreceptor, histone deacetylase 3, and peroxisome proliferator-activated receptor-? in human adipose tissue. Metab Syndr Relat Disord 10:312-7
Elbein, Steven C; Gamazon, Eric R; Das, Swapan K et al. (2012) Genetic risk factors for type 2 diabetes: a trans-regulatory genetic architecture? Am J Hum Genet 91:466-77
Rasouli, Neda; Kern, Philip A; Elbein, Steven C et al. (2012) Improved insulin sensitivity after treatment with PPAR? and PPAR? ligands is mediated by genetically modulated transcripts. Pharmacogenet Genomics 22:484-97

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