Aims: Obesity with related metabolic disturbances (eg. metabolic syndrome) increases cardiovascular disease risk and worsens outcomes in infarction/heart failure. Clinical studies however provide evidence of an “obesity paradox” which suggests that obesity per se may improve post myocardial infarct outcomes. The cellular basis of these effects however remains unclear. We test whether diet-induced obesity improves myocardial tolerance to ischaemia-reperfusion (I-R) and cytoprotective 'RISK' signalling in middle-aged (10 mth) rats exhibiting reduced insulin sensitivity. Methods and Results: Male Wistar rats were fed a control (CD) or high carbohydrate diet (HCD) for 32 weeks before assessing cardiac expression of pro-survival (Akt/PKB, ERK1/2, eNOS) and pro-injury (GSK3ß) enzymes, and responses to I-R in vivo (45 min left anterior descending (LAD) coronary artery occlusion/120 min reperfusion) and ex vivo (25 min ischaemia/60 min reperfusion). Compared to CD rats, age-matched HCD fed obese (OB) rats were heavier (764±25 vs. 657±22 gm; P<0.05) and hyperleptinaemic (11.1±0.7 vs. 5.0±0.7; P<0.01), with comparable insulin-insensitivity (HOMA-IR = 63.2±3.3 vs. 63.2±1.6 for CD). OB myocardium exhibited 40-60% higher expression and phosphorylation of Akt, a 20% increase in ERK1/2 phosphorylation, and 30-75% elevations in eNOS and glycogen synthase kinase 3 beta (GSK3ß) phosphorylation. In vivo infarct size was almost halved in OB (33±5%) vs. CD hearts (60±10%; P<0.05), as was ex vivo post-ischaemic LDH efflux (0.67±0.08 mU/ml vs. 1.55±0.32mU/ml; P<0.05) and contractile dysfunction (62±2% vs. 44±6% recovery of ventricular pressure; P<0.05). Conclusions: Dietary obesity improves myocardial I-R tolerance in middle-aged insulin-insensitive rats. These effects appear to involve modulation of pro-survival Akt, eNOS and ERK1/2, and injurious GSK3ß in obesity.