| dc.description.abstract | Resistin, endothelin-1 (ET-1), and suppressor of cytokine signaling protein-3 (SOCS-3) have been reported to regulate fat cell activity and insulin resistance, respectively. Previous reports showed that resistin could inhibit insulin action through activation of SOCS-3 protein. However, little are known about the signaling mechanisms of either resistin or ET-1 action on expression of adipocyte SOCS-3 gene. This study investigated the pathways involved in resistin and ET-1 modulation of SOCS-3 gene expression in 3T3-L1 adipocytes using the methods of both RT-PCR and real time-PCR. We found that resistin at 30 ng/ml for 2 h and ET-1 at 50 and 100 nM for 4 h induced increases in SOCS-3 mRNA levels, respectively. In addition, pretreatment with the inhibitors, including AG490 (a JAK inhibitor), an Uo126 (ERK inhibitor), SB203580 (a p38 MAPK inhibitor), SP60015 (a JNK inhibitor), Wortmannin (a PI3K inhibitor), LY294002 (a PI3K inhibitor), and epigallocatechin gallate (EGCG; an ERK inhibitor) inhibited either resistin or ET-1 stimulation of SOCS-3 mRNA levels. Treatment with each inhibitor alone did not significantly alter SOCS-3 mRNA expression, but U0126 alone significantly increased SOCS-3 levels. These data suggest that resistin and ET-1 stimulate SOCS-3 gene expression via the JAK-, ERK-, p38 MAPK-, JNK-, and PI3K-dependent pathways. Moreover, BQ610 (an ETA receptor inhibitor), but not BQ788 (an ETB receptor inhibitor), blocked ET-1-increased SOCS-3 mRNA levels, while treatment with each inhibitor alone did not alter SOCS-3 levels. This suggests the ETAR-dependent and ETBR-independent effect of ET-1. Interestingly, pretreatment with resistin reduced ET-1-increased SOCS-3 mRNA levels, pretreatment with ET-1 increased further resistin-induced increases in SOCS-3 levels. These data suggest that resistin and ET-1 can antagonistically interact to mediate expression of adipocyte SOCS-3 gene and their interactive effects likely depend on a common kinase pathway.
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