Obesity and its co-morbidities (dyslipidaemia, insulin resistance and hypertension) that together constitute the metabolic syndrome (MetS) are all risk factors for ischaemic heart disease (IHD). Although obesity has been reported to be an independent risk factor for congestive heart failure (CHF), whether obesity induced heart failure develops in the absence of increased afterload (induced by hypertension) is not clear. We have previously shown that obesity with insulin resistance decreases myocardial tolerance to ischaemia/reperfusion but the mechanisms for this decreased tolerance remains unclear. We hypothesise that obesity with insulin resistance induces: 1) adverse cardiac remodelling and pump dysfunction and, 2) adverse changes in myocardial pro-survival RISK pathway signalling to reduce myocardial tolerance to ischaemia/reperfusion. Wistar rats were fed an obesogenic (Obese) or a standard rat chow diet (Control) for 30 weeks. Echocardiography was performed over the 32 weeks before isolated Langendorff perfused hearts were subjected to 40 min coronary artery ligation followed by reperfusion and functional recovery (Rate Pressure Product-RPP), infarct size, and RISK pathway function assessed (Western blot analysis). Obesity with insulin resistance increased myocardial lipid accumulation but had no effect on in vivo or ex vivo left ventricular structure/function. Hearts from obese rats had lower reperfusion RPPs (13115ᵶ2 bpmmmHg for obese vs. 17781ᱱ09 bpmmmHg for control, p<0.05) and larger infarcts (36.3ᵮ6% of AAR in obese vs. 14.1Ხ8% of area at risk in control rats, p<0.01) as compared to control hearts. These changes were associated with reductions in RISK pathway function with 30-50%, and 40-60% reductions in Akt and GSK-3ߠexpression and phosphorylation respectively in obese rat hearts compared to controls. Total eNOS expression was reduced by 25% in obese rats. We conclude that obesity with insulin resistance had no effect on basal cardiac structure or function but decreased myocardial tolerance to ischaemia/reperfusion. This reduction in ischaemic tolerance was likely due to compromised RISK pathway function in obese insulin resistant animals.