Effect of peroxisome proliferator-activated receptor-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue

Objective: This study was designed to examine the effect of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands on the inflammatory changes induced by the interaction between adipocytes and macrophages in obese adipose tissue. Methods and Procedures: PPAR-alpha ligands (Wy-14,643 and fenofibrate) were added to 3T3-L1 adipocytes, RAW264 macrophages, or co-culture of 3T3-L1 adipocytes and RAW264 macrophages in vitro, and monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) mRNA expression and secretion were examined. PPAR-alpha ligands were administered to genetically obese ob/ob mice for 2 weeks. Moreover, the effect of PPAR-alpha ligands was also evaluated in the adipose tissue explants and peritoneal macrophages obtained from PPAR-alpha-deficient mice. Results: In the co-culture of 3T3-L1 adipocytes and RAW264 macrophages, PPAR-alpha ligands reduced MCP-1 and TNF-alpha mRNA expression and secretion in vitro relative to vehicle-treated group. The anti-inflammatory effect of Wy-14,643 was observed in adipocytes treated with macrophage-conditioned media or mouse recombinant TNF-alpha and in macrophages treated with adipocyte-conditioned media or palmitate. Systemic administration of PPAR-alpha ligands inhibited the inflammatory changes in adipose tissue from ob/ob mice. Wy-14,643 also exerted an anti-inflammatory effect in the adipose tissue explants but not in peritoneal macrophages obtained from PPAR-alpha-deficient mice. Discussion: This study provides evidence for the anti-inflammatory effect of PPAR-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue, thereby improving the dysregulation of adipocytokine production and obesity-related metabolic syndrome.