1626-P: Activation of Cardiac Mitochondrial Akt1 Enhanced Myocardial Fatty Acid Utilization, Protected against Diabetic Cardiomyopathy, and Improved Whole Body Fat Distribution

Abstract

Insulin stimulates Akt1 translocation to cardiac mitochondria, and we have recently shown that inhibition of cardiac mitochondria Akt1 led to mitochondrial dysfunction and cardiomyopathy. However, whether activation of mitochondrial Akt1 in cardiac muscle can protect against the development of diabetic cardiomyopathy is not known. To this end, we have generated an inducible heart-specific transgenic mouse harboring a mitochondria-targeting constitutively active Akt1 (CAMCAKT). Long-term high fat-high fructose diet (HFFD) caused myocardial hypertrophy, fibrosis and ventricular dysfunction in control mice, but the impact of HFFD were attenuated in the CAMCAKT mice. After just two months on HFFD, expression of Col1a1 and Col3a1 in CAMCAKT mice were lower than controls (p<0.01). After five months on HFFD, ejection fraction in CA mice was 17 % higher than in controls while fractional shortening was 22% higher (p<0.05). This indicated that activation of mitochondrial Akt protected myocardium against the development of cardiomyopathy in diet-induced diabetes. Metabolically, cardiac mitochondrial Akt1 increased fatty acid uptake in the cardiac muscle, which resulted in redistribution of whole-body fatty acid metabolism. Dynamic PET scans revealed a 65% increase (p<0.001) in heart uptake of fatty acid reporter [18F]fluoro-4-thia-oleate in CAMCAKT mice. CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and expended 13% more energy, compared to controls (p<0.05). Interestingly, fatty liver was reduced in the CAMCAKT mice (p<0.05), suggesting that cardiac mitochondrial Akt modulated fat deposition in the liver by higher myocardial fatty acid metabolism. In summary, activating cardiac mitochondrial Akt protected against diabetic cardiomyopathy, attenuated fatty liver, and induced whole body metabolism in this murine model of diet-induced diabetes. Disclosure A.Ta: None. Y.Chen: None. J.Li: None. E.Salem: None. P.H.Wang: Research Support; ViaCyte, Inc. Funding National Institutes of Health (R01HL096987); Ko Family Foundation