Identification of Signaling Pathways Involved in Aberrant Production of Adipokines in Adipocytes Undergoing Oxidative Stress

Background and Aims: In obesity, oxidative stress is responsible for the aberrant production of adipokines such as adiponectin, plasminogen activator inhibitor (PAI)-1 and interleukin-6 (IL-6), which is causally associated with obesity-related inflammation, insulin resistance and cardiovascular disease. However, the signaling transduction pathways participating in adipokine dysregulation induced by oxidative stress are largely unknown. Thus, the aim of the present study was to identify possible involved signaling pathways. Methods: 3T3-L1 cells were differentiated into adipocytes and underwent oxidative stress by exposure to extraneous H2O2. Quantitative PCR and immunoassays were performed to determine mRNA and protein levels of adipokines (adiponectin, PAI-1 and IL-6), respectively. Possible signaling pathways involved were high-throughout identified by Bioplex phosphoprotein assays and subsequently confirmed by inhibition of the targeted protein kinases such as Akt, ERK1/2, JAK/STAT, JNK, and p70 S6K, respectively. Results: H2O2 markedly suppressed adiponectin mRNA expression as well as protein secretion; however, it enhanced PAI-1 and IL-6 production in mature adipocytes. Akt,JAK/STAT and ERK1/2 participated in the H2O2-induced increase of PAI-1 and IL-6 expression, whereas adiponectin expression was reduced by H2O2 via Akt and JAK/STAT. Conclusions: Akt and JAK/STAT are congenerous pathways through which oxidative stress downregulates adiponectin and upregulates PAI-1 and IL-6 expression. ERK1/2 participates not in H2O2-induced decrease of adiponectin expression, but in the increase of PAI-1 and IL-6. [Copyright &y& Elsevier]