| Insulin resistance is the hallmark characteristic of obesity, aging, metabolic syndrome and type 2 diabetes, all of which are major risk factors for cardiovascular disease. Clinical human studies and animal experiments have repeatedly demonstrated that perturbations in cardiac substrate metabolism in insulin-resistant states compromise cardiac function although the underlying mechanisms are not clear. AMP-activated protein kinase (AMPK) is thought to be a master regulator of cellular and whole body energy metabolism. In the heart, activation of AMPK stimulates glucose uptake and fatty acid oxidation via translocation of glucose transporter 4 (GLUT4) and inactivating acetyl CoA decarboxylase (ACC), respectively. Since AMPK activity is suppressed in insulin resistant states, it is now being recognized as a therapeutic target for treating metabolic disorders and cardiovascular diseases. My PhD project is to study the involvement of AMPK in cardiac contractile dysfunction associated with obesity and aging. Using mouse models of high fat diet induced obesity and aging, I tested the hypothesis that a deficiency in AMPK activity may compromise obesity and aging-induced cardiac dysfunction. Alterations in key molecules in both AMPK and insuling signaling pathways under high fat diet- and aging were explored. Chronic high fat diet challenge (including a model of pre-and postnatal high fat feeding) led to increased adiposity, glucose intolerance, insulin resistance and defects in cardiac contractile function as well as calcium handling. Further investigations revealed the cardiac abnormalities in the high-fat fed mice were associated with decreased AMPK activity, cardiac hypertrophy, reduced glucose uptake and fatty acid oxidation, and lipotoxicity. Furthermore, high fat diet feeding led to blunted insuling signaling (reduced Akt-AS160), mitochondrial dysfunction, excess IRS serine phosphorylation, increased endoplasmic reticulum (ER) stress proteins and apoptosis, respectively. Furthermore, AMPK deficiency accentuated aging-induced cardiac contractile dysfunction associated with ventricular hypertrophy, ROS generation and mitochondrial dysfunction, indicating a critical cardioprotective role for AMPK with advancing age. Taken together, these data provide some evidence of the effects of AMPK in cardiac function under metabolic stress conditions marked by insulin resistance. Disruption of AMPK signaling compromises metabolic adaptation of the heart to nutrient stress and leads to contractile dysfunction. |
