PPAR gamma and the control of adipogenesis
PPAR gamma and the control of adipogenesis
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DOI：
10.1016/s0300-9084(97)81500-3
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发表时间：
1997-02-01
期刊：
影响因子：
3.9
通讯作者：
Brun, R
中科院分区：
文献类型：
--
作者：
Spiegelman, BM;Hu, E;Brun, R
我们最近克隆了过氧化物酶体增殖物激活受体γ作为一个因子，结合到一个增强子，具有特异性的脂肪细胞。当异位表达时，PPAR γ将成纤维细胞转化为真正的前脂肪细胞。在应用活化剂或PPAR γ配体时，这些细胞分化成脂肪细胞。最近，我们一直在试图了解天然配体的性质，激活过氧化物酶体增殖物激活受体γ和蛋白质结构域，控制脂肪形成。关于配体，我们已经表明，一个不寻常的前列腺素，15-脱氧δ（12，14）PG J2，可以结合到PPAR γ和激活它。第二个转录因子，诱导早期分化，ADD 1/SREBP 1，似乎促进形成的PPAR γ配体。该分子是bHLH家族的一员，转染该分子可导致可作为PPAR γ配体的分子分泌。这种配体样活性对PPAR的γ同种型具有特异性。目前的研究正试图鉴定这些潜在的新型配体。关于PPARgamma的结构-功能，我们首先分析了PPARalpha、gamma和delta三种亚型的成脂活性。使用适当的激活剂，很明显，过氧化物酶体增殖物激活物受体γ具有最大的脂肪形成作用。在高水平的最强激活剂的作用下，PPARalpha可以成脂，而PPARdelta不刺激脂肪细胞分化。为了鉴定负责分化的PPARy的结构域，产生PPARy和PPARS之间的嵌合体并转染到成纤维细胞中。这允许分离该分子中负责分化的相对较小的区域。
We recently cloned PPAR gamma as a factor that binds to an enhancer which has specificity for adipose cells. When expressed ectopically, PPAR gamma converts fibroblasts into bona fide preadipose cells. Upon application of activators or PPAR gamma ligands, these cells differentiate into fat cells. Most recently, we have been trying to understand the nature of natural ligands that activate PPAR gamma and the protein domains that control adipogenesis. With regards to ligands, we have shown that an unusual prostanoid, 15-deoxy Delta(12,14)PG J2, can bind to PPAR gamma and activate it. A second transcription factor that is induced early in differentiation, ADD1/SREBP1, appears to promote the formation of PPAR gamma ligands. Transfection of this molecule, a member of the bHLH family, causes the secretion of molecules that can serve as ligands for PPAR gamma. This ligand-like activity is specific for the gamma isoform of PPAR. Current studies are attempting to identify these potentially novel ligands. With regard to structure-function of PPAR gamma, we first analyzed the adipogenic activity of the three isoforms of PPAR: alpha, gamma and delta. Using appropriate activators of each it is clear that PPAR gamma has the most adipogenic action. PPAR alpha can be adipogenic with high levels of the strongest activators and PPAR delta does not stimulate fat cell differentiation. To identify the domain(s) of PPAR gamma responsible for differentiation, chimeras between PPAR gamma and PPAR delta were created and transfected into fibroblasts. This has allowed the isolation of relatively small regions of this molecule that are responsible for differentiation.