Title: Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity Authors
|Boudina, Sihem - UNIVERSITY OF UTAH-SLC|
|Sena, Sandra - UNIVERSITY OF UTAH-SLC|
|O'Neill, Brian - UNIVERSITY OF UTAH-SLC|
|Tathireddy, Parkash - UNIVERSITY OF UTAH-SLC|
|Abel, E - UNIVERSITY OF UTAH-SLC|
Submitted to: Circulation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 8, 2005
Publication Date: October 1, 2005
Citation: Boudina, S., Sena, S., O'Neill, B.T., Tathireddy, P., Young, M.E., Abel, E.D. 2005. Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation. 112(17):2686-2695. Interpretive Summary: Obese people have an increased chance of developing heart disease. It has been suggested that increased levels of nutrients such as fat and glucose in the blood contribute towards this increased risk of heart disease. The purpose of this study was to determine whether changes in the ability of the heart to use fat and carbohydrate as fuels affects heart function in an animal model of obesity. Through examining hearts that have been removed from lean and obese mice, we find that hearts of obese animals have a decreased ability to generate usable energy from fuels such as carbohydrate and fat. Instead, hearts from obese mice waste energy, making them inefficient during contraction. This may help explain why heart disease develops in obese humans.
Technical Abstract: 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. 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. 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.