Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in Obesity

• DOI: 10.1161/circulationaha.105.554360
• Publication Date: 2005-10-26T08:04:06Z
• Authors: Sihem Boudina; Sandra Sena; Brian T. O’Neill; Prakash Tathireddy; Martin E. Young; E. Dale Abel
• Keywords: 2. Zero hunger; Myocardium; Mice, Obese; Mitochondria, Heart; Oxidative Phosphorylation; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Adenosine Triphosphate; Oxygen Consumption; 0302 clinical medicine; Animals; Obesity; Energy Metabolism

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 (MV̇ o 2 ) 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, MV̇ o 2 , mitochondrial respiration, and ATP synthesis were measured in 9-week-old ob/ob and control mouse hearts. Contractile function and MV̇ o 2 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 MV̇ o 2 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 MV̇ o 2 .