Rosiglitazone-induced mitochondrial biogenesis in white adipose tissue is independent of peroxisome proliferator-activated receptor γ coactivator-1α.
Rosiglitazone-induced mitochondrial biogenesis in white adipose tissue is independent of peroxisome proliferator-activated receptor γ coactivator-1α.
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DOI：
10.1371/journal.pone.0026989
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Villena JA
中科院分区：
文献类型：
--
作者：
Pardo R;Enguix N;Lasheras J;Feliu JE;Kralli A;Villena JA
噻唑烷二酮类药物是一类常用于治疗2型糖尿病的胰岛素增敏药物，被认为部分是通过转录共激活因子pGC-1α(Peroxisome Proplator-Actiated Receptorγ辅激活剂-1α)促进白色脂肪组织中线粒体的生物发生而发挥作用的。为了评估pGC-1α在控制罗格列酮诱导的线粒体生物发生中的作用，我们建立了一种在脂肪组织中缺乏pGC-1α表达的小鼠模型(pGC-1α-FAT-KO小鼠)。我们发现，参与氧化磷酸化、三羧酸循环或脂肪酸氧化的线粒体蛋白编码基因在野生型和pGC-1α-FAT-KO小鼠的白色脂肪组织中的表达相似。此外，pGC-1α的缺失并没有阻止罗格列酮对线粒体基因表达或生物发生的积极作用，但它排除了罗格列酮对白色脂肪组织中UCP1和其他棕色脂肪特异性基因的诱导。与体内研究结果一致，基础和罗格列酮诱导的3T3-L1脂肪细胞线粒体基因的表达不受pGC-1α表达下调的影响，但当pGC-1β的表达被特异性siRNA下调时，其表达受到抑制。这些结果表明，在白色脂肪组织中，PGC-1α对于基础和罗格列酮诱导的线粒体生物发生是必不可少的，但对于罗格列酮诱导的UCP1和其他棕色脂肪细胞特异性标志物的表达是必需的。我们的研究表明，pGC-1α在白色脂肪组织中棕色脂肪细胞的出现中起重要作用。我们的发现也提供了证据，PGC-1β而不是PGC-1α调节基础和罗格列酮诱导的白色脂肪细胞线粒体基因的表达。
Thiazolidinediones, a family of insulin-sensitizing drugs commonly used to treat type 2 diabetes, are thought to exert their effects in part by promoting mitochondrial biogenesis in white adipose tissue through the transcriptional coactivator PGC-1α (Peroxisome Proliferator-Activated Receptor γ Coactivator-1α). To assess the role of PGC-1α in the control of rosiglitazone-induced mitochondrial biogenesis, we have generated a mouse model that lacks expression of PGC-1α specifically in adipose tissues (PGC-1α-FAT-KO mice). We found that expression of genes encoding for mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle or fatty acid oxidation, was similar in white adipose tissue of wild type and PGC-1α-FAT-KO mice. Furthermore, the absence of PGC-1α did not prevent the positive effect of rosiglitazone on mitochondrial gene expression or biogenesis, but it precluded the induction by rosiglitazone of UCP1 and other brown fat-specific genes in white adipose tissue. Consistent with the in vivo findings, basal and rosiglitazone-induced mitochondrial gene expression in 3T3-L1 adipocytes was unaffected by the knockdown of PGC-1α but it was impaired when PGC-1β expression was knockdown by the use of specific siRNA. These results indicate that in white adipose tissue PGC-1α is dispensable for basal and rosiglitazone-induced mitochondrial biogenesis but required for the rosiglitazone-induced expression of UCP1 and other brown adipocyte-specific markers. Our study suggests that PGC-1α is important for the appearance of brown adipocytes in white adipose tissue. Our findings also provide evidence that PGC-1β and not PGC-1α regulates basal and rosiglitazone-induced mitochondrial gene expression in white adipocytes.
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