OBJECTIVE-In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVO 2 ) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated. RESEARCH DESIGN AND METHODS-Oxygen consumptionand cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H 2 O 2 generation determined in isolated mitochondria.RESULTS-db/db hearts exhibited reduced cardiac function and increased MVO 2 . Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H 2 O 2 production was increased. Mitochondria from db/db mice exhibited fatty acid-induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 ␣-subunit of ATP synthase was reduced.CONCLUSIONS-These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from ␤-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.

Background-Obesity is a risk factor for cardiovascular disease and is strongly associated with insulin resistance and type 2 diabetes. Recent studies in obese humans and animals demonstrated increased myocardial oxygen consumption (MV O 2 ) and reduced cardiac efficiency (CE); however, the underlying mechanisms remain unclear. The present study was performed to determine whether mitochondrial dysfunction and uncoupling are responsible for reduced cardiac performance and efficiency in ob/ob mice. Methods and Results-Cardiac

Background-Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction and oxidative stress, which may contribute to left ventricular dysfunction. The contribution of altered myocardial insulin action, independent of associated changes in systemic metabolism, is incompletely understood. The present study tested the hypothesis that perinatal loss of insulin signaling in the heart impairs mitochondrial function. Methods and Results-In 8-week-old mice with cardiomyocyte deletion of insulin receptors (CIRKO), inotropic reserves were reduced, and mitochondria manifested respiratory defects for pyruvate that was associated with proportionate reductions in catalytic subunits of pyruvate dehydrogenase. Progressive age-dependent defects in oxygen consumption and ATP synthesis with the substrate glutamate and the fatty acid derivative palmitoyl-carnitine were observed. Mitochondria also were uncoupled when exposed to palmitoyl-carnitine, in part as a result of increased reactive oxygen species production and oxidative stress. Although proteomic and genomic approaches revealed a reduction in subsets of genes and proteins related to oxidative phosphorylation, no reductions in maximal activities of mitochondrial electron transport chain complexes were found. However, a disproportionate reduction in tricarboxylic acid cycle and fatty acid oxidation proteins in mitochondria suggests that defects in fatty acid and pyruvate metabolism and tricarboxylic acid flux may explain the mitochondrial dysfunction observed. Conclusions-Impaired myocardial insulin signaling promotes oxidative stress and mitochondrial uncoupling, which, together with reduced tricarboxylic acid and fatty acid oxidative capacity, impairs mitochondrial energetics. This study identifies specific contributions of impaired insulin action to mitochondrial dysfunction in the heart. (Circulation. 2009; 119:1272-1283.)Key Words: insulin Ⅲ metabolism Ⅲ mitochondria Ⅲ oxidative stress R ecent studies have suggested that impaired mitochondrial energetics may contribute to cardiac dysfunction in obesity and diabetes mellitus. [1][2][3][4][5][6][7] The pathogenesis of mitochondrial dysfunction in obesity or diabetes-related heart disease is likely multifactorial but includes fatty acid (FA)-mediated mitochondrial uncoupling and oxidative damage. 3,4,8 -11 A commonly associated finding in the heart in experimental models of obesity and diabetes mellitus is myocardial insulin resistance. [12][13][14][15][16] However, it is not known whether myocardial insulin resistance per se contributes directly to the pathogenesis of myocardial mitochondrial dysfunction. Clinical Perspective p 1283The effects of myocardial insulin signaling on the acute regulation of myocardial metabolism are well known 17,18 and include increasing glucose uptake and glycolysis via regulation of GLUT4 translocation 19,20 and activation of 6-phosphofructo-1-kinase. 21 In perfused hearts, insulin increases glucose oxidation and reduces FA oxidation. 13 In vivo, the antilipolytic ef...

No abstract