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

We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPAR alpha. We hypothesized that the PPAR alpha coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) 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 alpha deficient (PGC-1 alpha(-/-)) 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 alpha(-/-) and Ob/Ob-PGC-1 alpha(-/-) hearts lacked a mitochondrial biogenic response. PGC-1 alpha 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 alpha(-/-) 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 alpha upregulation. Animals that were deficient for PGC-1 alpha and heterozygous for the related coactivator PGC-1 beta (PGC-1 alpha(-/-)beta(+/-)) were bred to the Ob/Ob mice. Ob/Ob-PGC-1 alpha(-/-)beta(+/-) 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 adds. (C) 2011 Elsevier Ltd. All rights reserved.