title: Serum amyloid A attenuates cellular insulin sensitivity by increasing JNK activity in 3T3-L1 adipocytes.
abstract: 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.
authors.affiliation: Department of Endocrinology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors.forename: X Y
authors.initials: XY
authors.lastname: Ye
authors.forename: Y M
authors.initials: YM
authors.lastname: Xue
authors.forename: J P
authors.initials: JP
authors.lastname: Sha
authors.forename: C Z
authors.initials: CZ
authors.lastname: Li
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Zhen
mesh_terms: D041721:3T3-L1 Cells / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose