Project 4:The overall goal of this project remains to study the interactions between autonomic andmetabolic mechanisms involved in cardiovascular regulation. In this funding period we propose to determinethe role of the autonomic nervous system in the cardiovascular and metabolic abnormalities associated withobesity and the metabolic syndrome. It is postulated that obesity leads to a compensatory increase insympathetic activity intended to increase energy expenditure and lipolysis. Indeed, muscle sympatheticnerve activity, a direct measurement of baroreflex-modulated sympathetic outflow, is positively correlated tobody weight and visceral fat. We propose, however, that sympathetic activation not only fails to improve themetabolic abnormalities associated with obesity, but it is detrimental and contributes to cardiovascular andmetabolic complications. We have previously shown that autonomic withdrawal with the ganglionic blockertrimethaphan can be used to reveal human forms of sympathetically-dependent and -independenthypertension. Our preliminary data using this paradigm suggest that the autonomic nervous system is theprimary determinant of the increase in blood pressure associated with obesity, but contributes little, if any, toincreasing resting energy expenditure or lipolysis. We have also observed an increase in markers ofinflammation (CRP) and oxidative stress (F2-isoprostanes) in obesity and other conditions characterized bysympathetic activation, and, conversely, a decrease in these markers in patients with low sympatheticfunction. Based on these preliminary observations, we hypothesize that the increased sympathetic activitypresent in obesity contributes to hypertension, impaired lipolysis, insulin resistance, andinflammation/oxidative stress associated with this disorder. To test this hypothesis we propose to comparethe effects of acute and chronic sympathoinhibition, in lean and obese patients with hypertension, and innormal controls. Proving that the sympathetic activation associated with obesity does not result incompensatory beneficial metabolic effects, but is detrimental because it contributes to the cardiovascularand inflammatory/oxidatie stress abnormalities associated with this condition, may lead to a more effectivetreatment.
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