S 26948:: A new specific peroxisome proliferator-activated receptor γ modulator with potent antidiabetes and antiatherogenic effects
S 26948:: A new specific peroxisome proliferator-activated receptor γ modulator with potent antidiabetes and antiatherogenic effects
复制标题
DOI：
10.2337/db06-1734
复制
发表时间：
2007-11-01
期刊：
影响因子：
7.7
通讯作者：
Penicaud, Luc
中科院分区：
文献类型：
--
作者：
Carmona, Maria Carmen;Louche, Katie;Penicaud, Luc
目的：罗格列酮显示出强大的抗糖尿病作用，但与体重增加和脂肪生成有关。考虑到选择性过氧化物酶体增殖激活受体(PPAR) γ调节剂的概念，本研究的目的是表征一种新的PPAR γ配体s26948的特性，并特别关注体重增加。研究设计和方法：采用瞬时转染和结合实验表征s26948的结合特性，并采用GST下拉实验研究其与罗格列酮的共激活物募集模式。我们还利用3T3-F442A细胞系评估了其体外致脂能力及其在ob/ob小鼠（抗糖尿病和抗肥胖特性）以及纯合子人载脂蛋白E2敲入小鼠（E2- ki）（抗动脉粥样硬化能力）中的体内效应。结果：s26948具有高选择性PPAR γ配体的药理特征，但促进脂肪细胞分化的作用较弱。与罗格列酮相比，它也显示出不同的共激活剂招募特征，不能招募DRIP205或PPAR γ共激活剂。体内实验表明，s26948在改善葡萄糖和脂质稳态方面与罗格列酮一样有效，但没有增加体和白色脂肪组织重量，也没有改善肝脏脂质氧化。此外，s26948是PPAR γ配体中为数不多的能够减少动脉粥样硬化病变的分子之一。结论：这些研究结果表明，s26948是一种选择性PPAR γ配体，具有独特的共激活子招募和基因表达谱，降低了脂肪生成效应，并改善了体内生物反应。
OBJECTIVE-Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipogenesis. Keeping in mind the concept of selective peroxisome proliferator-activated receptor (PPAR)gamma modulator, the aim of this study was to characterize the properties of a new PPAR gamma ligand, S 26948, with special attention in body-weight gain.RESEARCH DESIGN AND METHODS-We used transient transfection and binding assays to characterized the binding characteristics of S 26948 and GST pull-down experiments to investigate its pattern of coactivator recruitment compared with rosiglitazone. We also assessed its adipogenic capacity in vitro using the 3T3-F442A cell line and its in vivo effects in ob/ob mice (for antidiabetes and antiobesity properties), as well as the homozygous human apolipoprotein E2 knockin mice (E2-KI) (for antiatherogenic capacity).RESULTS-S 26948 displayed pharmacological features of a high selective ligand for PPAR gamma with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPAR gamma coactivator-lot. In vivo experiments showed that S 26948 was as efficient in ameliorating glucose and lipid homeostasis as rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver. In addition, S 26948 represented one of the few molecules of the PPAR gamma ligand class able to decrease atherosclerotic lesions.CONCLUSIONS-These findings establish S 26948 as a selective PPAR gamma ligand with distinctive coactivator recruitment and gene expression profile, reduced adipogenic effect, and improved biological responses in vivo.