Small-Molecule Activators of AMP-Activated Protein Kinase (AMPK), RSVA314 and RSVA405, Inhibit Adipogenesis
Small-Molecule Activators of AMP-Activated Protein Kinase (AMPK), RSVA314 and RSVA405, Inhibit Adipogenesis
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DOI：
10.2119/molmed.2011.00163
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发表时间：
2011-09-01
影响因子：
5.7
通讯作者：
Marambaud, Philippe
中科院分区：
文献类型：
--
作者：
Vingtdeux, Valerie;Chandakkar, Pallavi;Marambaud, Philippe
amp活化蛋白激酶（AMPK）是细胞能量代谢的传感器和调节剂，可能与多种疾病有关，包括肥胖和阿尔茨海默病。它在控制关键代谢酶中的作用使该激酶成为葡萄糖和脂质稳态的中心参与者。最近，通过筛选与天然多酚白藜芦醇结构相似的合成小分子文库，我们鉴定出RSVA314和RSVA405是有效的AMPK间接激活剂（半最大有效浓度(EC50) = 1 μ mol/L）。本研究表明，在未分化和增殖的3T3-L1脂肪细胞中，RSVA314和RSVA405可以显著激活AMPK并抑制乙酰辅酶a羧化酶（ACC）， ACC是AMPK的靶点之一，也是脂肪酸生物发生的关键调节因子。我们发现，RSVA314和RSVA405处理通过干扰脂肪前细胞增殖过程中的有丝分裂克隆扩增来抑制3T3-L1脂肪细胞的分化（半最大抑制浓度(IC50) = 0.5 mu mol/L）。RSVA314和RSVA405阻止了脂肪生成过程中涉及的多种基因产物的脂肪生成依赖性转录变化，包括过氧化物酶体增殖物激活受体(PPAR)- γ。CCAAT/增强子结合蛋白α (C/EBP α)、脂肪酸合成酶、脂肪酸结合蛋白4 （aP2）、RANTES或抵抗素。此外，口服RSVA405（20和100 mg/kg/d）可显著降低高脂饲料小鼠的体重增加。这项工作表明，新的小分子AMPK激活剂（RSVA314和RSVA405）是有效的脂肪生成抑制剂，因此可能具有治疗肥胖的潜力。(C) 2011范斯坦医学研究所，www.feinsteininstitute.org在线地址：http://www.molmed.org doi: 10.2119/molmed.2011.00163
AMP-activated protein kinase (AMPK) is a sensor and regulator of cellular energy metabolism potentially implicated in a broad range of conditions, including obesity and Alzheimer's disease. Its role in the control of key metabolic enzymes makes this kinase a central player in glucose and lipid homeostasis. Recently, by screening a library of synthetic small molecules selected for their structural similarity with the natural polyphenol resveratrol, we identified RSVA314 and RSVA405 as potent indirect activators of AMPK (half-maximal effective concentration (EC50) = 1 mu mol/L in cell-based assays). Here we show that RSVA314 and RSVA405 can significantly activate AMPK and inhibit acetyl-CoA carboxylase (ACC), one target of AMPK and a key regulator of fatty acid biogenesis, in nondifferentiated and proliferating 3T3-L1 adipocytes. We found that RSVA314 and RSVA405 treatments inhibited 3T3-L1 adipocyte differentiation by interfering with mitotic clonal expansion during preadipocyte proliferation (half-maximal inhibitory concentration (IC50) = 0.5 mu mol/L). RSVA314 and RSVA405 prevented the adipogenesis-dependent transcriptional changes of multiple gene products involved in the adipogenic process, including peroxisome proliferator-activated receptor (PPAR)-gamma. CCAAT/enhancer-binding protein alpha (C/EBP alpha), fatty acid synthase, fatty acid binding protein 4 (aP2), RANTES or resistin. Furthermore, orally administered RSVA405 at 20 and 100 mg/kg/d significantly reduced the body weight gain of mice fed a high-fat diet. This work shows that the novel small-molecule activators of AMPK (RSVA314 and RSVA405) are potent inhibitors of adipogenesis and thus may have therapeutic potential against obesity. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00163