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Mitochondrial energetics in the heart in obesity related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins

¹Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112
²Department of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84112

Correspondence: dale.abel{at}hmbg.utah.edu

Objective.: In obesity and diabetes, myocardial fatty acid (FA) utilization and myocardial oxygen consumption (MVO₂) are increased and cardiac efficiency (CE) is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities; but has not been directly demonstrated.

Research Design and Methods.: Oxygen consumption and 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 H₂O₂ generation determined in isolated mitochondria.

Results.: db/db hearts exhibited reduced cardiac function and increased MVO₂. Mitochondrial ROS generation, lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired but H₂O₂ production was increased. Mitochondria from db/db mice exhibited FA-induced mitochondrial uncoupling that is inhibitable by GDP suggesting that these changes are mediated by uncoupling proteins. Mitochondrial uncoupling was not associated with an increase in uncoupling protein content, but FAO genes and expression of electron transfer flavoproteins were increased whereas the content of the F1 alpha- subunit of ATP synthase was reduced.

Conclusion.: These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of uncoupling proteins independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from beta-oxidation to the electron transport chain, which coupled with decreased OXPHOS capacity increases ROS production and lipid peroxidation.

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