The broad objectives of the proposed research are to determine mechanisms for reduced responsiveness to cardiac Beta-adrenergic stimulation in obesity and mechanisms whereby exercise training during the development of obesity may attenuate these effects. We hypothesize that obesity causes alterations in hemodynamics, cardiac hypertrophy, cardiac collagen, hormonal profile, and systolic function that are independent of hypertension. To test this hypothesis, we will compare lean rabbits with obese rabbits that develop hypertension along with obesity, and obese rabbits in which blood pressure will be controlled at pre-obese values using oral Hydralazine. We will use acute and chronic (telemetry) measurement of heart rate and blood pressure, as well as colored microspheres, to study hemodynamics. We will use western blotting techniques, blood sampling, wet and dry cardiac weights, and the Langendorff isolated heart preparation to analyze collagen, hormonal profile, cardiac hypertrophy, and systolic function. We also hypothesize that decreased cardiac responsiveness to Beta-adrenergic stimulation in obesity is due to abnormalities both at the cardiac Beta-receptor and in the G-coupled protein cascade leading to cAMP formation and calcium release from the sarcoplasmic reticulum. We will use appropriate assay and western blotting techniques to provide an analysis of the role of beta-receptor and post-receptor components such as Beta-receptor/Gs coupling, Gs stimulation of adenylate cyclase; formation of cAMP; activation of PKA, and sarcoplasmic reticulum calcium handling in contributing to cardiac abnormalities in obesity. We hypothesize that exercise training during development of obesity will 1) attenuate or prevent obesity-related hypertension, resting tachycardia, neurohumoral activation, and cardiac collagen formation and 2) attenuate obesity-related decreases in responsiveness to Beta-adrenergic stimulation. Abnormalities occurring in sedentary obese rabbits will be compared with their reduction in obese rabbits that undergo 12 weeks of treadmill exercise. Comparisons will also be made with appropriate lean controls. Finally, we will determine mechanisms within the Beta-adrenergic signaling pathway responsible for exercise-mediated increased responsiveness to Beta-adrenergic stimulation in obesity, using appropriate assay and western blotting techniques as noted above. Insight into possible mechanisms whereby obesity causes increased risk for development of congestive heart failure may lead to important advances in therapeutics modalities for prevention and treatment of congestive heart failure in obese patients. Further, information on mechanisms whereby regular endurance exercise may improve cardiovascular risk profile and cardiac performance in obesity may help reduce risk development of cardiovascular disease. Because such a large segment of the American population is overweight or obese, knowledge and insight gained from these studies can have far-reaching effects.
| Carroll, Joan F; Franks, Susan F; Smith, Adam B et al. (2009) Visceral adipose tissue loss and insulin resistance 6 months after laparoscopic gastric banding surgery: a preliminary study. Obes Surg 19:47-55 |
| Carroll, Joan F; Kaiser, Kathryn A; Franks, Susan F et al. (2007) Influence of BMI and gender on postprandial hormone responses. Obesity (Silver Spring) 15:2974-83 |
| Carroll, Joan F; Zenebe, Woineshet J; Strange, Taylor B (2006) Cardiovascular function in a rat model of diet-induced obesity. Hypertension 48:65-72 |
| Carroll, Joan F; Thaden, Jeremy J; Wright, Allison M et al. (2005) Loss of diurnal rhythms of blood pressure and heart rate caused by high-fat feeding. Am J Hypertens 18:1320-6 |
| Carroll, Joan F; Thaden, Jeremy J; Wright, Allison M (2005) A comparison of two exercise training programs on cardiac responsiveness to beta-stimulation in obesity. Exp Biol Med (Maywood) 230:180-8 |
| Carroll, J F; King, J W; Cohen, J S (2004) Hydralazine as antihypertensive therapy in obesity-related hypertension. Int J Obes Relat Metab Disord 28:384-90 |
| Carroll, Joan F; King, Jeffrey W; Cohen, Joshua S (2004) Hydralazine treatment alters body composition in the rabbit model of obesity. Acta Physiol Scand 181:183-91 |
| Carroll, Joan F (2003) Isolated heart responsiveness to beta-simulation after exercise training in obesity. Med Sci Sports Exerc 35:548-54 |
