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Epidemiological studies indicate that obesity, insulin resistance and diabetes are important comorbidities of patients with ischemic heart disease and increase mortality and development of congestive heart failure after myocardial infarction. Although ob/ob and db/db mice are commonly used to study obesity with insulin resistance or diabetes, mutations in the leptin gene or its receptor are rarely the cause of obesity in humans, which is instead primarily a consequence of dietary and lifestyle factors. Therefore, we used a murine model of diet-induced obesity to examine physiological effects of obesity and the inflammatory and healing response of diet-induced obese (DIO) mice after ischemia–reperfusion injury. DIO mice developed hyperinsulinemia and insulin resistance and hepatic steatosis, with significant ectopic lipid deposition in the heart and cardiac hypertrophy in the absence of significant changes in blood pressure. The mRNA levels of chemokines at 24 hours and cytokines at 24 and 72 hours of reperfusion were higher in DIO mice than lean mice. In the granulation tissue at 72 hours of reperfusion, macrophage density was significantly increased, while neutrophil density was reduced in DIO mice compared with lean mice. At 7 days of reperfusion, infarcted DIO mice ha