Obesity is frequently accompanied by insulin resistance and is associated with metabolic abnormalities, namely hyperglycemia, increased plasma free fatty acid (FFA) concentrations, and ectopic accumulation of lipid metabolites in nonadipose tissues such as skeletal muscle, liver, and heart. There is growing evidence that excessive lipid accumulation in cardiomyocytes is toxic and contributes significantly to cardiac disorders commonly associated with obesity and/or diabetes (1
Fatty acids (FAs) are the preferred substrate for ATP generation in a normal healthy heart (2
), and the rate of FA uptake and oxidation is regulated at multiple levels. The adult heart has the metabolic capability to switch substrate preferences in various pathological conditions. When the heart is stressed either physiologically or pathologically, a series of adaptive responses are normally activated; metabolic remodeling is one of the foremost. In fact, we have proposed that metabolic remodeling precedes, triggers, and sustains subsequent functional and structural remodeling (3
). A significant characteristic of the maladapted heart is loss of this metabolic flexibility. Increased reliance on any one metabolic pathway, along with reduced capacity for substrate switching, has been associated with accumulation of lipid species in the cardiomyocyte. For example, in diabetes, the heart almost exclusively relies on FA oxidation (FAO) (4
), whereas in hypoxic conditions (6
) and hypertrophy (7
), glucose utilization increases. Both conditions are associated with lipid accumulation within cardiomyocytes. Surplus accumulation of lipid species in cardiomyocytes has been shown to be associated with tissue dysfunction in genetic and transgenic animal models of obesity and diabetes (8
). Our recent observation in heart failure patients with nonischemic disease suggests that intramyocardial lipid deposition is a feature in diabetic patients with obesity (10
). These findings tie in with the long suggested argument that development and progression of heart failure is related to abnormalities in myocardial substrate metabolism.
We have previously described a murine model of ischemic cardiomyopathy induced by brief (15 min) daily repetitive ischemia and reperfusion (I/R), which does not result in myocardial necrosis but is associated with development of interstitial fibrosis and ventricular dysfunction (11
). Both ventricular dysfunction and cardiac fibrosis are reversible upon discontinuation of the ischemic protocol. The histological findings in the mouse closely resembled the pathology of human reversible ischemic cardiomyopathy that is associated with myocardial hibernation (11
). Induction of reactive oxygen species (ROS) is a critical early event that regulates processes such as the expression of the chemokine MCP-1 and subsequent inflammatory response, fibrosis, and ventricular dysfunction (11
). In addition, ROS regulate mRNA expression of antioxidant enzymes, FA metabolism, and myosin isoform genes (13
). Our previous findings in this model suggest that downregulation of peroxisome proliferator activated receptor–α (PPAR-α) expression and FAO are elements of an adaptive response that prevent lipotoxicity in repetitive I/R despite the fact that occlusion occurs only 15 min/day and is not accompanied by infarction (11
). Although it is clear that diet-induced obesity is associated with cardiac lipotoxicity, the role of accumulated lipid metabolites and metabolic adaptation in repetitive I/R injury has not been described. Obesity induced by a “Western” high-fat diet in C57BL/6J mice is associated with cardiac metabolic changes very similar to the diabetic heart, namely, increased expression of FA metabolism transcripts, increased capacity for FAO, and ectopic lipid accumulation. We hypothesized that dysregulation of adaptive responses in diet-induced obese (DIO) mice would enhance susceptibility to brief repetitive I/R.