Piceatannol, Natural Polyphenolic Stilbene, Inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation
Piceatannol, Natural Polyphenolic Stilbene, Inhibits Adipogenesis via Modulation of Mitotic Clonal Expansion and Insulin Receptor-dependent Insulin Signaling in Early Phase of Differentiation
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DOI：
10.1074/jbc.m111.259721
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发表时间：
2012-03-30
影响因子：
4.8
通讯作者：
Kim, Kee-Hong
中科院分区：
文献类型：
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作者：
Kwon, Jung Yeon;Seo, Sang Gwon;Kim, Kee-Hong
云杉醇是一种天然二苯乙烯类化合物，是白藜芦醇的类似物和代谢产物。尽管白藜芦醇在干预肥胖症的发展中具有良好的健康益处，但白藜芦醇在脂肪组织和相关疾病的发展中的作用尚不清楚。在这里，我们试图确定云杉烷醇在脂肪形成中的功能，并阐明其潜在的机制。我们发现，在非细胞毒性浓度下，Piceatannol以剂量依赖性方式抑制3 T3-L1前脂肪细胞的脂肪形成。云杉烷醇的这种抗脂肪形成特性在很大程度上限于脂肪形成的早期事件。在脂肪形成的早期阶段，经云杉醇处理的前体脂肪细胞在脂肪形成开始后24 h延迟进入G（2）/M期。此外，云杉醇抑制的有丝分裂克隆扩张伴随着胰岛素信号通路的激活减少。在脂肪形成的早期阶段，Piceatannol剂量依赖性地抑制分化混合物诱导的胰岛素受体（IR）/胰岛素受体底物-1（IRS-1）/Akt通路的磷酸化。此外，我们发现，云杉醇是IR激酶活性和磷脂酰肌醇3-激酶（PI 3 K）的抑制剂。我们的IR动力学研究进一步确定了ATP的Km值为57.8 μ M，Piceatannol的Ki值为28.9 μ M。我们还发现，云杉烷醇直接结合到IR和抑制IR激酶活性的混合非竞争性的方式ATP，通过该云杉烷醇似乎抑制脂肪形成。总而言之，我们的研究揭示了白藜芦醇的抗脂肪形成功能，并强调IR及其下游胰岛素信号传导是白藜芦醇在脂肪形成早期阶段的新靶点。
Piceatannol, a natural stilbene, is an analog and a metabolite of resveratrol. Despite a well documented health benefit of resveratrol in intervention of the development of obesity, the role of piceatannol in the development of adipose tissue and related diseases is unknown. Here, we sought to determine the function of piceatannol in adipogenesis and elucidate the underlying mechanism. We show that piceatannol inhibits adipogenesis of 3T3-L1 preadipocytes in a dose-dependent manner at noncytotoxic concentrations. This anti-adipogenic property of piceatannol was largely limited to the early event of adipogenesis. In the early phase of adipogenesis, piceatannol-treated preadipocytes displayed a delayed cell cycle entry into G(2)/M phase at 24 h after initiation of adipogenesis. Furthermore, the piceatannol-suppressed mitotic clonal expansion was accompanied by reduced activation of the insulin-signaling pathway. Piceatannol dose-dependently inhibited differentiation mixture-induced phosphorylation of insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/Akt pathway in the early phase of adipogenesis. Moreover, we showed that piceatannol is an inhibitor of IR kinase activity and phosphatidylinositol 3-kinase (PI3K). Our kinetics study of IR further identified a K-m value for ATP of 57.8 mu M and a K-i value for piceatannol of 28.9 mu M. We also showed that piceatannol directly binds to IR and inhibits IR kinase activity in a mixed noncompetitive manner to ATP, through which piceatannol appears to inhibit adipogenesis. Taken together, our study reveals an anti-adipogenic function of piceatannol and highlights IR and its downstream insulin signaling as novel targets for piceatannol in the early phase of adipogenesis.