This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity (body mass index >30kg/m2) affects more that 43 million Americans and is associated with increased cardiac morbidity and mortality. Abdominal obesity (AO) in particular, is associated with an increase in the incidence and manifestations of most of the common cardiac diseases or disorders, such as coronary artery disease and dilated cardiomyopathy. This is attributable, at least inpart, to the increased incidence in AO of known cardiac risk factors such as insulin resistance, type 2 diaetes mellitus and hypertension. Despite the known association between AO and cardiac disease, the mechanisms responsible for this association are poorly characterized in humans. Results of studies in experimental models of obesity suggest that increased adipose tissue lipolysis leading to increased fatty acid delivery and resultant insulin resistance, increase myocardial fatty acid uptake, utilization and oxidation. Ultimately, fatty acid uptake exceeds oxidation leading to intra-myocrdial accumulation of neutral lipids or truglycerides, which in turn has numerous effects of the myocyte leading to mtocardial systolic and diastolic function. Stable isotopic studies in humans with AO have demonstrated increased adiopose tissure lipolysis with increased release of ffatty acids in to plasma. Yet plasma fatty acid levels are frequently similar to that seen in lean individuals suggesting increased fatty acid uptake by non-adipose tissue. Whether the hearts of AO individuals exhibit and increase in fatty acid uptake as well as utilization and oxidation, and are susceptible to the changes observed in experimental models of obesity is unknown. We will address the following aims: 1A. Is myocardial fatty acid metaoblism altered and if so, how is it altered in relation to whole-body fatty acid kinetics? Because of the close-coupling between fatty acid and glucose metabolism in the heart, the relationship between myocardial glucose use adn whole-body glucose kineics will be assessed. Moreover, we will determine whether the changes in myocardial fatty acid metabolism observed with AO are associated with abnormalities in left ventricular systolic and diastolic function. 1B. The effect of significant weight loss (10% of body weight) on myocardial fatty acid and glucose metabolism in relation to whole-body fatty acid and glucose kinetics. In addition, we will assess whether the changes in myocardial substrate metabolism tha occur with weight loss are parallell by an improvement in left ventricular systolic and diastolic function: 2. Whether the response of myocardial fatty acid and glucose metabolism to increased insulin availability is altered and if so, how is it altered in relation to whole-body fatty acid and glucose kinetics? Moreover, we will determine the extent to which this myocardial metabolic response is associated with changes in left ventricular systolic and diastolic function and: 3. The impact of increased delivery of fatty acids on myocardial fatty acid and glucose metabolism in relation to whole-body fatty acid and glucose kinetics. We will also determine whether the myocardial metabolic response is associated with changes in left ventricular systolic and diastolic function. Successful completion of this project would provide important information about the myocardial metabolic alterations that occur with AO. Demonstration of enhanced myocardial fatty acid metabolism would provide confirmation that what is observed in experimental models of obesity is applicable to humand with AO. Moreover, demonstration of an association with systolic and diastolic abnormalities would provide evidence that this metabolic change may be or become maladaptive. Such information would provide a basis for more targeted studies designed to elucidate the mechanisms responsible for these phenomena. Moreover, demonstration that weight loss decreases fatty acid availability and thus, delivery which in turn reduces myocardial fatty acid metabolism and improves mechanical function would provide potential targets for novel therapies. Such therapies might include the use of either PPARy agonists to reduce peripheral lipolysis of PPARa agonists to increase fatty acid oxidation and reduce triglyceride formation. An example of a clinical ramification would be decreasing the dependence of the myocardium on fatty metabolism might reduce the susceptibility of myocardium to the effects of myocardial ischemia thus, reducing the excessive mortality associated with coronary artery disease in the people with obesity.
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