High-Throughput Screening for Small-Molecule Adiponectin Secretion Modulators
High-Throughput Screening for Small-Molecule Adiponectin Secretion Modulators
复制标题
DOI：
10.1177/1087057111403474
复制
发表时间：
2011-07-01
影响因子：
--
通讯作者：
Ido, Motoharu
中科院分区：
文献类型：
--
作者：
Hino, Kyosuke;Nagata, Hidetaka;Ido, Motoharu
脂联素是由脂肪细胞分泌的脂肪因子，在抑制可导致2型糖尿病、肥胖和动脉粥样硬化的代谢紊乱中起作用。一些研究表明，脂联素的上调具有许多治疗益处。虽然过氧化物酶体增殖物激活受体γ（PPAR γ）激动剂已知在培养的脂肪细胞和人类中增加脂联素分泌，但它们具有若干副作用，如体重增加、充血性心力衰竭和水肿。因此，不具有PPAR γ激动活性的脂联素分泌调节剂似乎有希望用于许多病症。在这里，作者报告了一种基于荧光素酶的高通量筛选（HTS）试验的发展，该试验使用胰岛素抵抗模拟3 T3-L1脂肪细胞来发现脂联素分泌调节剂。他们使用该模型筛选了大约10万种小分子化合物的文库，进行了几次后续筛选，并确定了6种增加脂联素分泌而不具有PPAR γ激动活性的命中化合物。这些化合物可能是用于糖尿病、肥胖症、动脉粥样硬化和其它代谢综合征的有用的候选药物。这种HTS测定可能适用于筛选其他脂肪因子调节剂，可用于治疗其他疾病。（Journal of Biomolecular Screening 2011; 16：628-636）
Adiponectin is an adipokine secreted by adipocytes and plays a role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. Several studies have shown that upregulation of adiponectin has a number of therapeutic benefits. Although peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are known to increase adiponectin secretion both in cultured adipocytes and humans, they have several side effects, such as weight gain, congestive heart failure, and edema. Therefore, adiponectin secretion modulators that do not possess PPAR gamma agonistic activity seem to promising for a number of conditions. Here, the authors report on the development of a reporter-based high-throughput screening (HTS) assay using insulin-resistant-mimic 3T3-L1 adipocytes for discovery of adiponectin secretion modulators. They screened a library of approximately 100 000 small-molecule compounds using this model, performed several follow-up screens, and identified six hit compounds that increase adiponectin secretion without having PPAR gamma agonistic activity. These compounds may be useful drug candidates for diabetes, obesity, atherosclerosis, and other metabolic syndromes. This HTS assay might be applicable to screening for other adipokine modulators that can be useful for the treatment of other conditions. (Journal of Biomolecular Screening 2011; 16: 628-636)