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

Authors Sihem Boudina, Sandra Sena, Heather Theobald, Xiaoming Sheng, Jordan J. Wright, Xia Xuan Hu, Salwa Aziz, Josie I. Johnson, Heiko Bugger,Vlad G. Zaha and E. Dale Abel Submitted By E. Dale Abel on 9/24/2007 Status Published Journal Diabetes Year 2007 Date Published 10/1/2007 Volume : Pages 56(10) : 2457 - 2466 PubMed Reference Abstract 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.

Investigators with authorship
Name Institution E. Dale Abel University of Iowa

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