Abstract 10854: Aleglitazar, a Balanced Dual PPAR alpha/ gamma Agonist, Decreases Lipolysis and Cytokine Production in a Cellular Model of Inflamed Human Adipose Tissue.
Aleglitazar is a balanced dual peroxisome proliferator-activated receptor (PPAR) alpha/ gamma agonist, designed to optimize lipid and glycemic benefits. It is currently in Phase III development for reduction of morbidity and mortality in patients who have recently suffered an acute coronary syndrome (ACS) event and have type 2 diabetes. Subclinical inflammation, demonstrated by increases in plasma and adipose tissue concentrations of inflammatory mediators such as interleukin-6 (IL-6), IL-8, monocyte chemotactic factor-1 (MCP-1) or tumor necrosis factor-alpha (TNF-alpha) and increased basal lipolysis, may contribute to the increased insulin resistance and cardiovascular risk of these patients. The Objectives of this study was to investigate the anti-inflammatory effects of aleglitazar in comparison to agonists selective for either PPAR-gamma (pioglitazone, 2.8 microM) or PPAR-alpha (fenofibric acid, 150 microM) in a co-culture system consisting of human adipocytes (SGBS-cells) and human macrophage-like cells (THP1-cells). This in vitro model displays many features of inflamed human adipose tissue including insulin resistance, increased basal lipolysis, increased inflammatory cytokine production, and alterations in adipokine secretion. After a 72 hour incubation, aleglitazar, but not pioglitazone or fenofibric acid, was able to reduce basal lipolysis by 80–90% in a dose-dependent manner at drug concentrations as low as 13nM. Aleglitazar, but not pioglitazone or fenofibric acid, reduced either expression or secretion of inflammatory cytokines including IL-6 (40–50%), IL-8 (30–40 %), MCP-1 (50–60 %) and PAI-1 (50–60%). Adiponectin, a marker for insulin sensitivity, was increased in SGBS-cells by 3-fold by aleglitazar, but only 1.5 fold by pioglitazone or fenofibric acid. In Conclusions, our data demonstrate that Aleglitazar strongly decreases multiple aspects of the inflamed phenotype of the human adipocyte/macrophage co-culture system compared to pioglitazone and fenofibrate. These data suggest that aleglitazar may benefit diabetic patients by reducing the underlying inflammatory cycle contributing to progression of adipose dysfunction and insulin resistance, and increased cardiovascular risk.
- © 2010 by American Heart Association, Inc.