These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-kappaB activation.

Objectives-Fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) or n-3 PUFAs have been shown to reduce the incidence of coronary heart disease. Here we investigated the effect of highly purified eicosapentaenoic acid (EPA) on production of adiponectin, the only established antiatherogenic and antiinflammatory adipocytokine, in rodent models of obesity and human obese subjects. Methods and Results-We demonstrated that EPA increases adiponectin secretion in genetically obese ob/ob mice and high-fat diet-induced obese mice. In the in vitro coculture of adipocytes and macrophages, EPA reversed the coculture-induced decrease in adiponectin secretion at least in part through downregulation of tumor necrosis factor-␣ in macrophages. We also showed significant increase in plasma adiponectin concentrations in human obese subjects after a 3-month treatment with EPA (1.8 g daily). Multivariate regression analysis revealed that EPA treatment is the only independent determinant of plasma adiponectin concentrations. Conclusion-This study demonstrates that EPA increases adiponectin secretion in rodent models of obesity and human obese subjects, possibly through the improvement of the inflammatory changes in obese adipose tissue. Because EPA has reduced the risk of major coronary events in a large-scale, prospective, randomized clinical trial, this study provides important insight into its therapeutic implication in obesity-related metabolic sequelae. (Arterioscler Thromb Vasc Biol. 2007;27:1918-1925.)Key Words: adipocytes Ⅲ adiponectin Ⅲ EPA Ⅲ macrophages Ⅲ obesity T he adipose tissue has a high capacity to secrete many biologically active substances (or adipocytokines) such as leptin and tumor necrosis factor-␣ (TNF␣). 1 Dysregulation of pro-and antiinflammatory adipocytokine production is associated with the metabolic syndrome, suggesting that inflammatory changes within obese adipose tissue may critically contribute to the development of many aspects of the metabolic syndrome and results in diabetes and atherosclerosis. Among numerous adipocytokines, adiponectin is unique in that it is the only established adipocytokine with antiatherogenic and antiinflammatory properties. 2,3 It also increases tissue fat oxidation, leading to reduced levels of fatty acids (FAs) and tissue triglyceride content, thus enhancing insulin sensitivity in the liver and skeletal muscle. 2,4,5 Because plasma adiponectin concentrations are decreased in obese subjects, 1,2 extensive researches have been aimed at the upregulation of adiponectin and its cognate receptors (AdipoR1 and AdipoR2) for the treatment of obesityrelated metabolic sequelae. 2 Previous studies showed that the adipose tissue is markedly infiltrated by macrophages in several models of rodent obesities and human obese subjects, 6,7 suggesting that macrophages participate in the inflammatory pathways that are activated in obese adipose tissue. Using an in vitro coculture system composed of adipocytes and macrophages, we have demonstrated that a paracrine loop involving saturate...