Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in Obesity
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Abstract
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 (MV̇o2) 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.
Methods and Results— Cardiac function, MV̇o2, mitochondrial respiration, and ATP synthesis were measured in 9-week-old ob/ob and control mouse hearts. Contractile function and MV̇o2 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 MV̇o2 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 MV̇o2.
Received April 6, 2005; revision received July 19, 2005; accepted August 8, 2005.
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- Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in ObesitySihem Boudina, Sandra Sena, Brian T. O’Neill, Prakash Tathireddy, Martin E. Young and E. Dale AbelCirculation. 2005;112:2686-2695, originally published October 24, 2005https://doi.org/10.1161/CIRCULATIONAHA.105.554360
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- Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in ObesitySihem Boudina, Sandra Sena, Brian T. O’Neill, Prakash Tathireddy, Martin E. Young and E. Dale AbelCirculation. 2005;112:2686-2695, originally published October 24, 2005https://doi.org/10.1161/CIRCULATIONAHA.105.554360