Role of Cardiac Steatosis and Lipotoxicity in Obesity Cardiomyopathy

Abstract

See related article, pp 216–222 The pandemic of obesity is a devastating health problem and contributes to premature morbidity and mortality. Results from clinical and experimental studies have identified a variety of unfavorable consequences of obesity including cardiovascular diseases, pulmonary diseases, cancer, and sleep disorders. An obesity-triggered parallel increase in the prevalence of type 2 diabetes mellitus is also expected to add to the overall cardiovascular burden of obesity. Components of metabolic syndrome such as dyslipidemia, hyperglycemia, insulin resistance, and hypertension are thought to play pivotal roles in obesity-associated sequelae responsible for atherosclerosis, cardiac hypertrophy, and ventricular dysfunction. The presence of 1 or more of these metabolic syndrome components can adversely affect multiple metabolic pathways resulting in alterations in glucose and lipid metabolism, fatty acid (FA) transport/storage/oxidation, oxygen consumption, redox status, and high-energy phosphate metabolism. Although the precise mechanism(s) of action responsible for metabolic derangement-induced cardiac abnormalities in obesity remains poorly understood, 1 theory that has received increasing attention focuses on lipid transport and storage, excessive FA oxidation (FAO), and lipotoxic injury to the heart.1,2 When energy intake exceeds expenditure, fat is stored as triacylglycerol (TG) in adipose tissue. In turn, once fat levels exceed the storage capacity of adipocytes, a variety of neutral lipids are released and accumulated in other cells and tissues including the heart. The presence of lipid inclusions within cardiomyocytes, a condition referred to as cardiac steatosis, has been confirmed in obesity and diabetes.3,4 Although recent evidence indicates that cardiac steatosis, increased availability of FA and excess FAO contribute to cardiac anomalies associated with obesity and type 2 diabetes, it has also been suggested that cardiac steatosis may be a compensatory mechanism used to neutralize FAs and their metabolites through esterification to neutral lipids. Generation of ATP for normal cardiac …