| dc.description.abstract | Resistin and endothelin (ET)-1 have been reported to inhibit adipogenesis and
regulate adipocyte insulin resistance, respectively. Recent studies have
demonstrated that resistin stimulated ET-1 expression and that ET-1
time-dependently stimulated resistin secretion, but the exact signaling pathway of
ET-1 to act on resistin gene expression is still unknown. In this study, we
investigated the signaling pathways involved in ET-1-stimulated resistin gene
expression in 3T3-L1 adipocytes. ET-1 up-regulated resistin mRNA expression in
dose- and time-dependent manners. The concentration of ET-1 that increased
resistin mRNA levels by 100-250% was approximately 100 nM after 0.25~12 h.
Treatment with actinomycin-D blocked ET-1-increased resistin mRNA levels,
suggesting that the effect of ET-1 requires new mRNA synthesis. Because ET-1 did
not alter the basal half-life of resistin mRNA induced by acti-D alone,
ET-1-stimulated resistin expression is unlikely due to through altered mRNA stability.
Treatment with an inhibitor of endothelin type A receptor (ETAR), such as BQ610,
but not with ETBR antagonist BQ788, blocked ET-1-increased levels of resistin
mRNA and phosphorylated levels of downstream signaling molecules, such as
ERK1/2, JNKs, AKT, and STAT3. Moreover, pre-treatment of specific inhibitors of
either ERK1/2 (U0126 and PD98059), JNKs (SP600125), PI3K/AKT (LY294002 and
wortmannin), or JAK2/STAT3 (AG490) prevented ET-1-increased levels of resistin
mRNA and respectively reduced ET-1-stimulated phosphorylation of ERK1/2, JNKs,
AKT and STAT3. However, p38 kinase antagonist SB203580 did not block the effect
of ET-1. These results suggest that ETAR, ERK1/2, JNKs, AKT, and STAT3, but not
ETBR or p38, are necessary for the ET-1 stimulation of resistin gene expression.
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