Abstract 282: Increasing Cardiac Fatty Acid Oxidation Protects Against High Fat Diet Induced Mitochondria Dysfunction and Cardiomyopathy in Mice

Abstract

In the obese and diabetic heart, an imbalance between fatty acid uptake and fatty acid oxidation (FAO) promotes the development of cardiac lipotoxicity. In this study, we tested the hypothesis that enhancing FAO via 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. 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 enhancing myocardial FAO via ACC2 deletion prevents HFD induced cardiac dysfunction and attenuates pathological hypertrophy in obese mice. We then examined the mitochondrial respiration activity under chow and HFD fed conditions. HFD feeding significantly reduced mitochondria oxygen consumption rate in Con hearts but not in iKO mice (332 vs. 418 pmoles/min, p<0.05, n=5), suggesting that enhancing FAO prevented HFD induced mitochondria dysfunction. In vitro, palmitate (PA) induced mitochondria fragmentation and increased reactive oxygen species production was partially attenuated in ACC2 knocked down cardiomyocyte. Knocking down of ACC2 also prevented PA induced cell death. Moreover, HFD treatment significantly reduced the expression of LC3 and p62 in mitochondria fraction, indicative of impaired mitophagy in obese mice, which was attenuated in iKO mice. Therefore, the beneficial effect for enhancing cardiac fatty oxidation in HFD induced obesity model is mediated, in part, by maintenance of mitochondrial function through regulating mitophagy activity. Taken together, our findings suggest that promoting cardiac FAO is an effective strategy to prevent the development of cardiac lipotoxicity during diet-induced obesity.