Inhibitory Effects of A-769662, a Novel Activator of AMP-Activated Protein Kinase, on 3T3-L1 Adipogenesis
Inhibitory Effects of A-769662, a Novel Activator of AMP-Activated Protein Kinase, on 3T3-L1 Adipogenesis
复制标题
A-769662（一种新型 AMP 激活蛋白激酶激活剂）对 3T3-L1 脂肪生成的抑制作用
DOI：
10.1248/bpb.32.993
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发表时间：
2009-06-01
影响因子：
2
通讯作者：
Wu, Donghai
中科院分区：
文献类型：
--
作者：
Zhou, Yi;Wang, Dongye;Wu, Donghai
AMP激活的蛋白激酶(AMPK)是糖脂代谢的核心分子，但其在脂肪细胞分化中的作用尚不清楚。A-769662是一种新的AMPK激活剂，在体内通过增加脂肪酸氧化和减少脂肪酸合成而减少体重增加，降低肝脏和血浆甘油三酯水平。在本研究中，我们利用3T3-L1细胞研究了A-769662对脂肪细胞分化的影响。我们发现A-769662通过下调成脂相关转录因子和成脂标记物的表达，显著抑制3T3-L1分化。抑制作用主要发生在分化早期，通过抑制细胞有丝分裂克隆扩张(MCE)而发挥作用，而MCE是脂肪形成所必需的。A-769662也降低了分化和成熟的3T3-L1脂肪细胞的细胞活力。此外，用A-769662诱导3T3-L1细胞分化后，AMPK过度激活，导致脂肪酸合成和利用的重要酶--乙酰辅酶A羧化酶的磷酸化和失活增加。综上所述，这些结果表明，A-769662通过多种方式抑制3T3-L1成脂分化，因此可能是治疗肥胖的一种有前途的化合物。
AMP-activated protein kinase (AMPK) is a central player in glucose and lipid metabolism while its role in adipocyte differentiation remains obscure. A-769662, a novel activator of AMPK, has been implicated to reduce body weight gain and decrease liver and plasma triglyceride levels via increasing fatty acid oxidation and reducing fatty acid synthesis in vivo. In this study, we examined the effects of A-769662 on adipocyte differentiation using 3T3-L1 cells. We found that A-769662 significantly inhibited 3T3-L1 differentiation via down-regulation of adipogenesis-related transcription factors and adipogenic markers. The inhibitory effect mainly occurred at the early phase of differentiation through inhibition of mitotic clonal expansion (MCE), which was essential for adipogenesis. A-769662 also decreased cell viability of differentiating and mature 3T3-L1 adipocytes. Moreover, treatment of differentiating 3T3-L1 cells with A-769662 resulted in AMPK over-activation, which led to an increased phosphorylation and inactivation of acetyl-CoA carboxylase (ACC), an important enzyme for the synthesis and usage of fatty acids. Taken together, these results suggest that A-769662 inhibits 3T3-L1 adipogenic differentiation in several ways and therefore may be a promising compound for the treatment of obesity.