Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity.
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 (MVO2) 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.


RESULTS
Cardiac function, MVO2, mitochondrial respiration, and ATP synthesis were measured in 9-week-old ob/ob and control mouse hearts. Contractile function and MVO2 in glucose-perfused ob/ob hearts were similar to controls under basal conditions but were reduced under high workload. Perfusion of ob/ob hearts with glucose and palmitate increased MVO2 and reduced CE by 23% under basal conditions, and CE remained impaired at high workload. In glucose-perfused ob/ob hearts, mitochondrial state 3 respirations were reduced but ATP/O ratios were unchanged. In contrast, state 3 respiration rates were similar in ob/ob and control mitochondria from hearts perfused with palmitate and glucose, but ATP synthesis rates and ATP/O ratios were significantly reduced in ob/ob, which suggests increased mitochondrial uncoupling. Pyruvate dehydrogenase activity and protein levels of complexes I, III, and V were reduced in obese mice.


CONCLUSIONS
These data indicate that reduced mitochondrial oxidative capacity may contribute to cardiac dysfunction in ob/ob mice. Moreover, fatty acid but not glucose-induced mitochondrial uncoupling reduces CE in obese mice by limiting ATP production and increasing MVO2.
Boudina
Sihem
S
Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Sena
Sandra
S
O'Neill
Brian T
BT
Tathireddy
Prakash
P
Young
Martin E
ME
Abel
E Dale
ED
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology*
D000255:Adenosine Triphosphate