Abstract 10: Increasing Cardiac Fatty Acid Oxidation Protects Against High Fat Diet Induced Cardiomyopathy in Mice

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In the obese and diabetic heart, an imbalance between fatty acid uptake and fatty acid oxidation (FAO) promotes the development of cardiac lipotoxicity. We previously demonstrated that cardiac-specific deletion of ACC2 in adult mice was effective in increasing myocardial FAO while maintaining normal cardiac function and energetics. In this study, we tested the hypothesis that ACC2 deletion in an adult heart would prevent the cardiac lipotoxic phenotype in a mouse model of diet-induced obesity. ACC2 flox/flox (CON) and ACC2 flox/flox-MerCreMer+ (iKO) were injected with tamoxifen and subjected to a high fat diet (HFD) for 24 weeks. HFD induced similar body weight gain and glucose intolerance in CON and iKO. In isolated Langendorff-perfused heart experiments, HFD feeding increased FAO 1.6-fold in CON mice which was further increased to 1.9-fold in iKO mice compared with CON on chow diet. HFD induced systolic and diastolic dysfunction was abolished in iKO mice compared with CON mice (Fractional shortening 32.8±2.8% (CON) vs. 39.2±3.2% (iKO), E’/A’ ratio 0.91±0.09 (CON) vs. 1.11±0.08 (iKO), p< 0.05, n=5-6). Heart weight /Tibia length ratio was significantly higher in CON than iKO mice after HFD feeding (7.19±0.22 vs. 6.47±0.28, p<0.05, n=6). These data indicate that elevated myocardial FAO per se does not cause the development of cardiac dysfunction in obese animals. In fact, enhancing FAO via ACC2 deletion prevents HFD induced cardiac dysfunction and attenuates pathological hypertrophy. Molecular markers for ER stress such as p-PERK (1.5 fold) and p-JNK (2 fold) was elevated in CON-HFD hearts, which was completely attenuated in iKO-HFD hearts. Impairment of autophagy was also observed in CON-HFD hearts evidenced by decreases in LC3 II (60%) and increases in P62 (75%) level, while no difference in autophagy were observed in iKO-HFD hearts compared to iKO-chow. Therefore, the beneficial effect for enhancing cardiac fatty oxidation in HFD induced obesity model may be mediated, in part, by maintenance of cellular homeostasis and survival through regulating ER stress and autophagy. Taken together, our findings suggest that promoting cardiac FAO is an effective strategy to resist the development of cardiac lipotoxicity during diet-induced obesity.