Phillyrin, a Natural Lignan, Attenuates Tumor Necrosis Factor α-Mediated Insulin Resistance and Lipolytic Acceleration in 3T3-L1 Adipocytes

In obese adipose tissue, tumor necrosis factor-alpha secreted from macrophages plays an important role in the adipocyte dysfunctions, including insulin resistance, lipolytic acceleration, and changes of adipokines, which promote the development of obesity-related complications. Phillyrin, an active ingredient found in many medicinal plants and certain functional foods, elicits anti-obesity and anti-inflammatory properties in vivo. The aim of the current study was to investigate the role of phillyrin in preventing tumor necrosis factor alpha-induced insulin resistance or lipolytic acceleration in 3T3-L1 adipocytes. Our results showed that phillyrin partially restored insulin-stimulated 2-DOG uptake, which was reduced by tumor necrosis factor-alpha, with concomitant restoration in serine phosphorylation of insulin receptor substrate-1 and insulin-stimulated Glut4 translocation to plasma membrane. Phillyrin also dose-dependently prevented tumor necrosis factor alpha-stimulated adipocyte lipolysis with preserved downregulation of perilipin. The mitogen-activated protein kinases and I kappaB kinase activation was promoted in tumor necrosis factor alpha-stimulated adipocytes, but pretreatment with 40 mu M phillyrin inhibited the phosphorylation of extracellular signal-regulated kinases1/2, stress-activated protein kinase/Jun N-terminal kinase and I kappaB kinase (p<0.05). Moreover, phillyrin could inhibit the expressions of interleukin-6 and monocyte chemoattractant protein-1 induced by tumor necrosis factor-alpha. Using transwell coculture method with 3T3-L1 adipocytes and RAW 264.7 macrophages, the enhanced productions of tumor necrosis factor-alpha and free fatty acids in the medium were significantly reduced by phillyrin (p<0.05). These results indicate that phillyrin exerts a beneficial effect on adipocyte dysfunctions induced by tumor necrosis factor-alpha through suppression of the activation of I kappaB kinase and N-terminal kinase. Phillyrin may have the potential to ameliorate the inflammatory changes and insulin resistance in obese adipose tissue.