Abstract 6257: High-Fat-Diet Induced Cardiomyocyte Dysfunction in AMPK-deficient Mice
Introduction: Obesity is an independent risk factor for cardiovascular disease. Data from our lab and others showed that diet-induced obesity (DIO) causes cardiomyocyte dysfunction. AMP-activated protein kinase (AMPK) is a fuel gauge of intracellular and whole body energy. When activated, AMPK phosphorylates key regulatory enzymes of glucose and lipid metabolism. This study is designed to investigate the impact of AMPK deficiency in DIO-induced cardiomyocyte dysfunction and possible mechanisms.
Methods: Adult C57 wild-type (Wt, n=16) and transgenic (Tg, n=16) mice with cardiac-specific overexpression of a dominant-negative mutant AMPK α2 catalytic subunit were divided into 4 groups and fed a high- or low-fat diet for 20 weeks. Cardiomyocyte mechanical properties including peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR90, ±dL/dt) were determined using an IonOptix® system. Protein expression of total AMPK, p-AMPK, p-ACC, Akt, and p-Akt was performed using Western blot.
Results: High fat diet-induced obesity led to glucose intolerance and compromised glucose uptake in high fat diet-fed Wt and Tg groups. Intriguingly, cardiomyocytes from high-fat-fed Tg mice showed more pronounced depression in contractile function including decreased PS, ±dL/dt and prolonged TR90 compared with myocytes from high-fat-fed Wt mice. Western blot analysis revealed that high fat feeding down-regulated p-ACC and pAkt expression in hearts from high fat-fed Tg mice compared to Wt mice.
Conclusion: These data suggest that a synergistic effect between AMPK deficiency and DIO in cardiac dysfunction, possibly associated with defective Akt/ AMPK signaling.