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(Circulation. 2005;112:2686-2695.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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

Sihem Boudina, PhD; Sandra Sena, PhD; Brian T. O’Neill, BS; Prakash Tathireddy, BS; Martin E. Young, DPhil; E. Dale Abel, MB, BS, DPhil

From the Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology and Genetics (S.B., S.S., B.T.O., P.T., E.D.A.), University of Utah School of Medicine, Salt Lake City, Utah, and USDA/ARS Children’s Nutrition Research Center and Department of Pediatrics (M.E.Y.), Baylor College of Medicine, Houston, Tex.

Correspondence to E. Dale Abel, MB,BS, DPhil, Division of Endocrinology, Metabolism and Diabetes, Program in Human Molecular Biology & Genetics, 15 N 2030 E, Bldg 533, Room 3410B, Salt Lake City, UT 84112. E-mail dale.abel{at}hmbg.utah.edu

Received April 6, 2005; revision received July 19, 2005; accepted August 8, 2005.

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 (MO₂) 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, MO₂, mitochondrial respiration, and ATP synthesis were measured in 9-week-old ob/ob and control mouse hearts. Contractile function and MO₂ 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 MO₂ 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 MO₂.

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