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 PPARγagonists also have anti-inflammatory properties. In addition to their beneficial effects on serum lipids and heart disease, fish oils (ω-3 fatty acids) activate PPARγand demonstrate antiinflammatory 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 ω-3 fatty acids for 12 weeks. We will determine whether there is evidence of macrophage apoptosis in adipose tissue, and we will determine whether ω-3 fatty acids increases the level or secretion of adiponectin. Hypothesis 2. Anti-inflammatory effects of fish oils are mediated by activation of PPARγand/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 PPARγ inhibitor, and we will measure PPARγresponses, such as the secretion of HMW adiponectin and macrophage apoptosis. In addition, we will determine whether ω-3 fatty acids induce changes in recruitment of inflammatory receptors, such as toll-like receptor 4 (TLR4) and TNFαReceptor 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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080327-05
Application #
8274802
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Leschek, Ellen W
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$309,282
Indirect Cost
$101,011
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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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
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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Elbein, Steven C; Kern, Philip A; Rasouli, Neda et al. (2011) Global gene expression profiles of subcutaneous adipose and muscle from glucose-tolerant, insulin-sensitive, and insulin-resistant individuals matched for BMI. Diabetes 60:1019-29
Spencer, Michael; Unal, Resat; Zhu, Beibei et al. (2011) Adipose tissue extracellular matrix and vascular abnormalities in obesity and insulin resistance. J Clin Endocrinol Metab 96:E1990-8
Spencer, Michael; Yao-Borengasser, Aiwei; Unal, Resat et al. (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299:E1016-27
Unal, Resat; Yao-Borengasser, Aiwei; Varma, Vijayalakshmi et al. (2010) Matrix metalloproteinase-9 is increased in obese subjects and decreases in response to pioglitazone. J Clin Endocrinol Metab 95:2993-3001
Smith, Latasha M; Yao-Borengasser, Aiwei; Starks, Tasha et al. (2010) Insulin resistance in African-American and Caucasian women: differences in lipotoxicity, adipokines, and gene expression in adipose tissue and muscle. J Clin Endocrinol Metab 95:4441-8

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