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-diptheria 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-␣ (PPAR␣), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPAR␣ in the observed mitochondrial biogenesis response in the insulin-resistant heart. Insulin-resistant UCP-DTA mice crossed into a PPAR␣-null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPAR␣ exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPAR␣-driven mitochondrial biogenic response revealed that expression of PPAR␥ coactivator-1␣ (PGC-1␣), a known regulator of mitochondrial biogenesis, was activated in wild-type UCP-DTA mice but not in PPAR␣-deficient UCP-DTA mice. Conclusions-These

Background-Emerging evidence in obesity and diabetes mellitus demonstrates that excessive myocardial fatty acid uptake and oxidation contribute to cardiac dysfunction. Transgenic mice with cardiac-specific overexpression of the fatty acid-activated nuclear receptor peroxisome proliferator-activated receptor-␣ (myosin heavy chain [MHC]-PPAR␣ mice) exhibit phenotypic features of the diabetic heart, which are rescued by deletion of CD36, a fatty acid transporter, despite persistent activation of PPAR␣ gene targets involved in fatty acid oxidation. Methods and Results-To further define the source of fatty acid that leads to cardiomyopathy associated with lipid excess, we crossed MHC-PPAR␣ mice with mice deficient for cardiac lipoprotein lipase (hsLpLko). MHC-PPAR␣/hsLpLko mice exhibit improved cardiac function and reduced myocardial triglyceride content compared with MHC-PPAR␣ mice. Surprisingly, in contrast to MHC-PPAR␣/CD36ko mice, the activity of the cardiac PPAR␣ gene regulatory pathway is normalized in MHC-PPAR␣/hsLpLko mice, suggesting that PPAR␣ ligand activity exists in the lipoprotein particle. Indeed, LpL mediated hydrolysis of very-low-density lipoprotein activated PPAR␣ in cardiac myocytes in culture. The rescue of cardiac function in both models was associated with improved mitochondrial ultrastructure and reactivation of transcriptional regulators of mitochondrial function. Key Words: cardiomyopathy Ⅲ lipids Ⅲ diabetes mellitus T ype 2 diabetes mellitus and its associated cardiovascular complications are a worldwide health threat. 1,2 Although patients with obesity-related diabetes mellitus have an increased incidence of heart failure after myocardial infarction, 3 they are also prone to develop heart failure in the absence of significant coronary artery disease. 4 These observations suggest that myocardial dysfunction in diabetes mellitus, metabolic syndrome, and obesity has distinct pathogenic features. Conclusions-MHC-PPAR␣ Clinical Perspective on p 435Multiple mechanisms have been proposed to drive diabetes mellitus-associated heart dysfunction, including glucose toxicity (advanced glycation end products), 5 microvascular disease, 6 mitochondrial dysfunction, 7,8 and lipid toxicity. 9,10 Evidence supports a role for lipid metabolic derangements in the development of cardiomyocyte dysfunction in the insulinresistant and diabetic heart 9,10 ; both lipid accumulation and excessive fatty acid (FA) oxidation (FAO) are postulated to cause cardiomyocyte toxicity. Human studies and animal models demonstrate that diabetes mellitus and obesity are associated with accumulation of myocyte fat. 11,12 Additionally, the insulin-resistant heart is unable to fully use glucose, forcing the organ to rely on FAs, leading to a vicious cycle of increased myocyte FA import, oxidation, and triglyceride accumulation, 10 signatures of a metabolic cardiomyopathy called lipotoxic cardiomyopathy. Reprogramming of the insulin-resistant heart toward FA use involves gene regulatory mechanisms. Peroxisome proliferator-activated...