Obesity-associated co-morbidities include insulin resistance, glucose intolerance, diabetes mellitus, dyslipidemia, and cardiovascular disease (e.g., atherosclerosis, stroke, myocardial infarction, and heart failure) [1]. Cardiovascular disease is undoubtedly a major cause of death in metabolic disease patients, such as obese subjects [2]. In addition to ischemic heart disease, the state of obesity impairs both the form and function of the myocardium [3,4]. This condition, termed obesity cardiomyopathy, is often characterized by cardiac hypertrophy and impaired contractility (independent of adverse ischemic events) [5,6]. Determining the mechanisms contributing to this non-ischemic heart disease has proven elusive, due to the vast number of neurohumoral alterations in the obesity milieu. These include, but are not exclusive to, dyslipidemia and nutrient excess, chronic over-activation of sympathetic tone and the renin-angiotensin system (RAS), as well as imbalances in paracrine and endocrine factors (e.g., insulin and leptin) [6,7]. At the molecular level, the heart often presents increased reactive oxygen and nitrogen species, elevated lipotoxic species (e.g., ceramide), altered gene and microRNA expression, endoplasmic reticulum (ER) stress, autophagy, disrupted calcium homeostasis, mitochondrial dysfunction, and marked perturbations in metabolic fluxes [1]. The imbalance between nutrient supply, utilization, and clearance that is commonly observed during obesity can lead to death of cells (including cardiomyocytes) [8]. If not corrected, these events can ultimately culminate in the development of dilated cardiomyopathy.
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