A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity
A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity
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DOI：
10.1016/s1097-2765(01)00353-7
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发表时间：
2001-10-01
期刊：
影响因子：
16
通讯作者：
Auwerx, J
中科院分区：
文献类型：
--
作者：
Rocchi, S;Picard, F;Auwerx, J
Fmoc-L-亮氨酸(F-L-Leu)是一种独特的PPAR-γ配体。两个F-L-亮氨酸分子结合到单个PPARγ分子的配体结合域上，使其受体相互作用模式有别于其他核受体配体。F-L-亮氨酸诱导PPAR-γ的特殊变构构型，导致不同的辅因子募集和翻译具有不同的药理特性。F-L-亮氨酸激活PPAR-γ的效力低于罗格列酮，但最大效力与罗格列酮相似。F-L-亮氨酸诱导的特定的PPAR伽马构型导致了靶基因激活的修饰模式。F-L-亮氨酸改善正常、饮食诱导的糖耐量低减和糖尿病db/db小鼠的胰岛素敏感性，但其成脂活性较低。这些生物学效应表明，F-L-亮氨酸是一种选择性的PPAR伽马调节剂，它激活了一些(胰岛素敏化)，但不是所有(脂肪生成)PPAR伽马信号通路。
FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPAR gamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPAR gamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPAR gamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPAR gamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPAR gamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPAR gamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPAR gamma -signaling pathways.