已有研究指出，抗胰島素激素　（ｒｅｓｉｓｔｉｎ　和第一型內皮素（ｅｎｄｏｔｈｅｌｉｎ－１）　會抑制脂肪分化以及與脂肪細胞的胰島素抗性有關。　最近的研究也指出，抗胰島素激素會刺激第一型內皮素表現；第一型內皮素會刺激抗胰島素激素分泌，而此作用具有時間的效應。但第一型內皮素刺激抗胰島素基因表現的作用機制目前仍不清楚。本篇研究中，我們以３Ｔ３－Ｌ１脂肪細胞中首度討論第一型內皮素會刺激抗胰島素激素ｍＲＮＡ表現的訊息路徑。第一型內皮素所促進的抗胰島素ｍＲＮＡ表現，具有劑量與時間效應。１００　ｎＭ　的第一型內皮素的作用下，０．２５～１２　小時所促進的抗胰島素ｍＲＮＡ表現約為１００～２５０％。而前處理Ａｃｔｉｎｏｍｙｃｉｎ　Ｄ則會抑制了第一型內皮素所增加的抗胰島素ｍＲＮＡ表現，此結果支持了第一型內皮素作用需要新ｍＲＮＡ的合成。由於，第一型內皮素並未改變在Ａｃｔｉｎｏｍｙｃｉｎ　Ｄ作用之下的抗胰島素激素ｍＲＮＡ半衰期，所以推論第一型內皮素並不是透過改變ｍＲＮＡ穩定性而增加抗胰島素激素ｍＲＮＡ的表現量。前處理Ａ型內皮素受器　ＥＴＡＲ　抑制劑，如ＢＱ６１０，拮抗了第一型內皮素所增加的抗胰島素激素ｍＲＮＡ表現和下游訊息分子的磷酸化，例如ＥＲＫ１卅２、ＪＮＫｓ、ＡＫＴ和　ＳＴＡＴ３等。但Ｂ型內皮素受器　（ＥＴＢＲ）抑制劑，如ＢＱ７８８，並沒有這樣的效果。此外，分別前處理如ＥＲＫ１卅２　（Ｕ０１２６　ａｎｄ　ＰＤ９８０５９），　ＪＮＫｓ　（ＳＰ６００１２５），　ＰＩ３Ｋ卅ＡＫＴ　（ＬＹ２９４００２　ａｎｄ　ｗｏｒｔｍａｎｎｉｎ），　ｏｒ　ＪＡＫ２卅ＳＴＡＴ３　（ＡＧ４９０）的抑制劑，抑制了內皮素所促進的抗胰島素激素ｍＲＮＡ表現，並且分別降低第一型內皮素所刺激的訊息分子磷酸化，如ＥＲＫ１卅２、ＪＮＫｓ、ＡＫＴ　和ＳＴＡＴ３。然而，ｐ３８激酶抑制劑並未抑制第一型內皮素的作用。上述結果顯示，第一型內皮素刺激抗胰島素激素基因是透過ＥＴＡＲ，以及ＥＲＫ１卅２、ＪＮＫｓ、ＡＫＴ和ＳＴＡＴ３的活化，但ＥＴＢＲ和ｐ３８則不是必需的。

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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