SYSTOLIC CARDIAC FUNCTION IN OBESITY AND EXERCISE

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DESCRIPTION (Adapted from applicant's abstract) The candidate's immediate career goals are to study the role of the beta-receptor signaling pathway in mediating systolic dysfunction in obesity, and the role of exercise training in attenuating obesity-related cardiovascular defects. The Department of Integrative Physiology at the University of North Texas Health Science Center is uniquely suited to help the candidate achieve these goals. Within the department, there is a wide variety of expertise in human, animal, in vivo, and in vitro studies in cardiovascular physiology and endocrinology. This will aid in developing expertise with a variety of surgical, laboratory, and assay techniques to study cardiac function. Further, the Cardiovascular Research Institute at the University of North Texas Health Science Center provides access to research efforts of molecular biologists, pharmacologists, physiologists and physicians from within the institution and from nearby institutions. This will benefit career development by providing opportunities to integrate knowledge from many fields which impact cardiovascular research. The current proposal has three major goals: 1) to determine mechanisms associated with reduced cardiac contractile responsiveness to beta-adrenergic stimulation in obesity, 2) to determine the role of exercise training in attenuation of obesity-induced abnormalities in cardiac function, and 3) to determine the role of obesity, separate from hypertension, in contributing to systolic dysfunction in sedentary and trained animals. The investigators hypothesize that there are multiples sites of decreased activity in the beta- signaling pathway in obesity. Thus, they will use the rabbit method of dietary-induced obesity to compare function of lean animals with that of obese animals after 12 weeks of a high fat diet. They will use the Langendorff isolated heart preparation and appropriate assay and western blotting techniques to analyze the role of the beta-receptor and four sites of post- receptor activity in contributing to cardiac abnormalities in obesity. The investigators also hypothesize that exercise training during the development of obesity will attenuate or prevent obesity-related cardiovascular abnormalities. They will determine whether exercise training will 1) reduce obesity-related hypertension, resting tachycardia, and neurohumoral activation, and 2)attenuate obesity-related decreases in responsiveness to beta-adrenergic stimulation. They will examine hemodynamics and neurohumoral activation in vivo and use the isolated heart preparation to determine the role of exercise training in increasing responsiveness to beta-adrenergic stimulation. Finally, they hypothesize that obesity has an independent effect on cardiac hypertrophy and systolic dysfunction. They will test this hypothesis by maintaining blood pressure at control levels as obesity develops before testing for responsiveness to beta-adrenergic stimulation. Insight into mechanisms whereby obesity increases risk for congestive heart failure may lead to advances in therapeutic modalities for prevention and treatment of heart failure in obese patients. Information on mechanisms whereby exercise training may improve cardiovascular risk profile and cardiac performance in obesity may help reduce risk for development of cardiovascular diseases in obesity. Because such a large segment of the American population is overweight or obese, the knowledge and insight gained from these studies can have far-reaching effects.