The transcriptional coactivators, PGC-1¦Á and ¦Â, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance

详细信息    查看全文

• 作者：Riddhi Mitra^a ; ^b ; Daniel P. Nogee^a ; ^b ; Juliet F. Zechner^a ; ^b ; Kyungmoo Yea^c ; Carrie M. Gierasch^a ; Attila Kovacs^a ; Denis M. Medeiros^d ; Daniel P. Kelly^a ; ^c ; Jennifer G. Duncan^a ; ^b ; ^{duncan_j@wustl.edu}
• 关键词：PPAR ; peroxisome proliferator-activated receptor ; ERR ; estrogen related receptor ; PGC-1 ; PPAR gamma coactivator-1 ; FAO ; fatty acid oxidation ; FA ; fatty acid ; WT ; wild-type ; HF ; high fat ; NORC ; Nutrition Oriented Research Center ; WUSM ; Washington Universit
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 出版时间：March, 2012
• 年：2012
• 卷：52
• 期：3
• 页码：701-710
• 全文大小：1245 K

文摘

We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPAR¦Á. We hypothesized that the PPAR¦Á coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1¦Á) is necessary for mitochondrial biogenesis in insulin resistant hearts and that this response was adaptive. Mitochondrial phenotype was assessed in insulin resistant mouse models in wild-type (WT) versus PGC-1¦Á deficient (PGC-1¦Á^{??/sup>) backgrounds. Both high fat-fed (HFD) WT and 6 week-old Ob/Ob animals exhibited a significant increase in myocardial mitochondrial volume density compared to standard chow fed or WT controls. In contrast, HFD PGC-1¦Á??/sup> and Ob/Ob-PGC-1¦Á??/sup> hearts lacked a mitochondrial biogenic response. PGC-1¦Á gene expression was increased in 6 week-old Ob/Ob animals, followed by a decline in 8 week-old Ob/Ob animals with more severe glucose intolerance. Mitochondrial respiratory function was increased in 6 week-old Ob/Ob animals, but not in Ob/Ob-PGC-1¦Á??/sup> mice and not in 8 week-old Ob/Ob animals, suggesting a loss of the early adaptive response, consistent with the loss of PGC-1¦Á upregulation. Animals that were deficient for PGC-1¦Á and heterozygous for the related coactivator PGC-1¦Â (PGC-1¦Á??/sup>¦Â+/?/sup>) were bred to the Ob/Ob mice. Ob/Ob-PGC-1¦Á??/sup>¦Â+/?/sup> hearts exhibited dramatically reduced mitochondrial respiratory capacity. Finally, the mitochondrial biogenic response was triggered in H9C2 myotubes by exposure to oleate, an effect that was blunted with shRNA-mediated PGC-1 ¡°knockdown? We conclude that PGC-1 signaling is important for the adaptive cardiac mitochondrial biogenic response that occurs during the early stages of insulin resistance. This response occurs in a cell autonomous manner and likely involves exposure to high levels of free fatty acids.}