title: Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins.
abstract: 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.
  
  
  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 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 alpha-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 beta-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
authors.forename: Sihem
authors.initials: S
authors.lastname: Boudina
authors.forename: Sandra
authors.initials: S
authors.lastname: Sena
authors.forename: Heather
authors.initials: H
authors.lastname: Theobald
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sheng
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Xia Xuan
authors.initials: XX
authors.lastname: Hu
authors.forename: Salwa
authors.initials: S
authors.lastname: Aziz
authors.forename: Josie I
authors.initials: JI
authors.lastname: Johnson
authors.forename: Heiko
authors.initials: H
authors.lastname: Bugger
authors.forename: Vlad G
authors.initials: VG
authors.lastname: Zaha
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism / Q000648:ultrastructure; D006861:Hydrogen Peroxide; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D006861:Hydrogen Peroxide