A permanent increase in acute-phase serum amyloid A (A-SAA) level is observed in obesity and insulin resistance. Recently, A-SAA has been shown to correlate with obesity and insulin resistance in human. However, what triggers A-SAA up-regulation is poorly understood, and the mechanism of elevated A-SAA to insulin resistance has not been elucidated. In this study, we used two cellular models of insulin resistance, one induced by treatment with tumor necrosis factor-alpha (TNF-alpha) and the other with the glucocorticoid dexamethasone. Gene expression analysis showed that SAA3 mRNA levels were increased in both models of insulin resistance, and ELISA showed that A-SAA levels were increased in both models too. To assess the potential impact of A-SAA on insulin resistance, we treated 3T3-L1 adipocytes with recombinant human SAA (Rh-SAA) and found that Rh-SAA attenuated cellular insulin sensitivity, up-regulated the level of phosphor-JNK, and down-regulated the level of phosphotyrosine-IRS-1 and the expression of glucose transporter 4 (GLUT4) in 3T3-L1 adipocytes. Pre-treatment of cells with C-Jun amino-terminal kinases (JNK) inhibitor brought about partial restoration of Rh-SAA-induced insulin resistance. In sum, our findings suggest that serum amyloid A might be a marker of insulin resistance, and it might play a major role in the development of obesity-related insulin resistance. Moreover, in our study it has been proved that JNK is indeed a crucial component of the pathway responsible for SAA-induced insulin resistance in 3T3-L1 adipocytes, which suggests that a selective interference with JNK activity might be a useful strategy in the treatment of Type 2 diabetes and other insulin-resistant states.
