Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-α/PGC-1α Gene Regulatory Pathway

BACKGROUND: Obesity and diabetes mellitus are complex metabolic problems of pandemic proportion, contributing to significant cardiovascular mortality. Recent studies have shown altered mitochondrial function in the hearts of diabetic animals. We hypothesized that regulatory events involved in the control of mitochondrial function are activated in the prediabetic, insulin-resistant stage. METHODS AND RESULTS: Morphometric analyses demonstrated that cardiac myocyte mitochondrial volume density was increased in insulin-resistant uncoupling protein-diphtheria toxin A (UCP-DTA) transgenic mice, a murine model of metabolic syndrome, compared with littermate controls. Mitochondrial DNA content and expression of genes involved in multiple mitochondrial pathways were also increased in insulin-resistant UCP-DTA hearts. The nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPARalpha), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPARalpha in the observed mitochondrial biogenesis response in the insulin-resistant heart. Insulin-resistant UCP-DTA mice crossed into a PPARalpha-null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPARalpha exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPARalpha-driven mitochondrial biogenic response revealed that expression of PPARgamma coactivator-1alpha (PGC-1alpha), a known regulator of mitochondrial biogenesis, was activated in wild-type UCP-DTA mice but not in PPARalpha-deficient UCP-DTA mice. CONCLUSIONS: These results demonstrate that mitochondrial biogenesis occurs early in the development of diabetic cardiac dysfunction through a transcriptional regulatory circuit that involves activation of PGC-1alpha gene expression by the fatty acid-activated nuclear receptor PPARalpha.