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 17623815
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
NameInstitution
E. Dale AbelUniversity of Iowa

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