Abstract and Introduction
Abstract
Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks. Plasma macrophage chemoattractant protein 1 (MCP-1) levels were reduced by FO, but the levels of other cytokines were unchanged. The adipose (but not muscle) of FO-treated subjects demonstrated a decrease in macrophages, a decrease in MCP-1, and an increase in capillaries, and subjects with the most macrophages demonstrated the greatest response to treatment. Adipose and muscle ω-3 fatty acid content increased after treatment; however, there was no change in insulin sensitivity or adiponectin. In vitro, M1-polarized macrophages expressed high levels of MCP-1. The addition of ω-3 fatty acids reduced MCP-1 expression with no effect on TNF-α. In addition, ω-3 fatty acids suppressed the upregulation of adipocyte MCP-1 that occurred when adipocytes were cocultured with macrophages. Thus, FO reduced adipose macrophages, increased capillaries, and reduced MCP-1 expression in insulin-resistant humans and in macrophages and adipocytes in vitro; however, there was no measureable effect on insulin sensitivity.
Introduction
The development of type 2 diabetes represents a complex series of events that begins with the development of insulin resistance. The changes in adipose tissue that accompany obesity, the metabolic syndrome, and insulin resistance include increased adipose tissue macrophages, circulating inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6,[1–3] and the development of a chronic inflammatory state. In addition to the infiltration of macrophages, other changes occur in the adipose tissue of obese, insulin-resistant subjects, including an increase in extracellular matrix (ECM) components, such as collagen VI, thrombospondin, and collagen V and a decrease in elastin.[4–7] Along with adipocyte expansion, changes in the adipose vasculature have been described, including a decrease in capillaries and an increase in larger blood vessels,[7,8] leading to the hypothesis that adipocyte necrosis and inflammation develop as a result of adipocyte expansion into a relatively hypoxic, nonelastic ECM.[9]
Fish oils (FOs) are rich sources of ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and there is a large amount of literature on the potential benefits of FOs on lowering serum triglycerides, cardiovascular protection, and immune modulation. There is considerable evidence supporting the anti-inflammatory effects of ω-3 PUFAs,[10] and FOs may be an adjunct in the treatment of rheumatoid arthritis, inflammatory bowel disease, and asthma.[11,12] Although the mechanism of this effect is complex, part of the anti-inflammatory action involves an inhibition of the production of eicosanoids from arachadonic acid.[13] In addition, a number of studies have demonstrated that FOs have a peroxisome proliferator–activated receptor γ (PPARγ)–like effect.[14] PPARγ agonist drugs, such as the thiazolidinediones, improve insulin sensitivity and have anti-inflammatory properties. Previous studies have demonstrated thiazolidinedione-mediated reductions in plasma inflammatory markers and adipose tissue macrophages and an increase in blood adiponectin.[15–18] Although the effects of FOs on adipose inflammation are unknown, previous studies have generally not found that FOs improve insulin sensitivity in humans.[19]
This study was performed to determine whether FOs would ameliorate the adipose tissue inflammation, fibrosis, and vascular abnormalities that are found in subjects with obesity and insulin resistance. After 12 weeks of treatment with standard clinical doses of ω-3 PUFAs, we found a decrease in adipose tissue macrophages, an increase in adipose capillaries, and a decrease in macrophage chemoattractant protein 1 (MCP-1) levels.
Diabetes. 2013;62(5):1709-1717. © 2013 American Diabetes Association, Inc.
