BackgroundThiazolidinediones, 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).Methodology/Principal FindingsTo 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.Conclusions/SignificanceThese 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.
Proper development and function of white adipose tissue (WAT), which are regulated by multiple transcription factors and coregulators, are crucial for glucose homeostasis. WAT is also the main target of thiazolidinediones, which are thought to exert their insulin-sensitizing effects by promoting mitochondrial biogenesis in adipocytes. Besides being expressed in WAT, the role of the coactivator PGC-1β in this tissue has not been addressed. To study its function in WAT, we have generated mice that lack PGC-1β in adipose tissues. Gene expression profiling analysis of WAT reveals that PGC-1β regulates mitochondrial genes involved in oxidative metabolism. Furthermore, lack of PGC-1β prevents the induction of mitochondrial genes by rosiglitazone in WAT without affecting the capacity of thiazolidinediones to enhance insulin sensitivity. Our findings indicate that PGC-1β is important for basal and rosiglitazone-induced mitochondrial function in WAT, and that induction of mitochondrial oxidative capacity is not essential for the insulin-sensitizing effects of thiazolidinediones.
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