Risk estimates from the Framingham Heart Study indicate that ~75% of essential hypertension in men and 65% of essential hypertension in women is largely attributed to excess body weight and obesity. Convincing evidence from both clinical studies and animal models demonstrates that elevated sympathetic outflow to the kidney and hindlimb vasculature plays a pivotal role in the pathogenesis of obesity-induced hypertension. Despite the important relationship between body weight or adiposity and activation of the sympathetic nervous system, little is known regarding the neural pathways and cellular mechanisms that underlie the sustained increase in sympathetic outflow and arterial blood pressure during obesity. The long term goal of our laboratory is to identify the neural pathways and cellular mechanisms that increase sympathetic outflow and blood pressure in obesity. Two afferent signals to the brain postulated to mediate the elevated sympathetic outflow and blood pressure in obesity are hyperinsulinemia and hyperleptinemia. Our working hypothesis is that diet-induced obesity increases circulating insulin and leptin to activate a descending circuit from the arcuate nucleus to the hypothalamic paraventricular nucleus. Subsequent receptor activation in the hypothalamus increases the discharge of sympathetic neurons in the hypothalamic paraventricular nucleus to enhance excitatory drive to the brainstem and spinal cord. This enhanced excitatory drive increases sympathetic outflow and arterial blood pressure. In this application, we will use state-or-the-art electrophysiological approaches to identify the central mechanisms that support obesity-induced hypertension.
Specific aim 1 will identify the cellular mechanisms within the hypothalamic paraventricular nucleus by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow.
Specific Aim 2 will identify the cellular mechanisms within the rostral ventrolateral medulla by which hyperinsulinemia and hyperleptinemia increase sympathetic outflow.
Specific Aim 3 will identify the mechanisms within the hypothalamic paraventricular nucleus and rostral ventrolateral medulla that support the elevated sympathetic outflow and blood pressure in a rodent model of diet-induced obesity. Our rationale for this project is that identification of the neural pathways and mechanisms that mediate the sympathoexcitatory actions of insulin and leptin, and how these pathways ultimately contribute to obesity-induced hypertension will provide a framework for the development of novel therapeutic treatments. PROJECT NARRATIVE Recent risk estimates indicate that high blood pressure is largely attributed to excess body weight or obesity. This application will identify the mechanisms in the brain that link obesity and hypertension, and therefore provide a framework for the development of novel therapeutic treatments in obese individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090826-05
Application #
8217289
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2008-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$382,119
Indirect Cost
$134,619
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Stocker, Sean D; Gordon, Kathryn W (2015) Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol 113:1302-9
Steiner, Jennifer L; Bardgett, Megan E; Wolfgang, Lawrence et al. (2014) Glucocorticoids attenuate the central sympathoexcitatory actions of insulin. J Neurophysiol 112:2597-604
Stocker, Sean D; Muntzel, Martin S (2013) Recording sympathetic nerve activity chronically in rats: surgery techniques, assessment of nerve activity, and quantification. Am J Physiol Heart Circ Physiol 305:H1407-16
Stocker, Sean D; Monahan, Kevin D; Browning, Kirsteen N (2013) Neurogenic and sympathoexcitatory actions of NaCl in hypertension. Curr Hypertens Rep 15:538-46
Luckett, Brittany S; Frielle, Jennifer L; Wolfgang, Lawrence et al. (2013) Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin. Am J Physiol Heart Circ Physiol 304:H1538-46
Stocker, Sean D; Monahan, Kevin D; Sinoway, Lawrence I (2013) The hypothalamic paraventricular nucleus may not be at the heart of sympathetic outflow. J Physiol 591:1
Ward, Kathryn R; Bardgett, James F; Wolfgang, Lawrence et al. (2011) Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus. Hypertension 57:435-41
Bardgett, Megan E; McCarthy, John J; Stocker, Sean D (2010) Glutamatergic receptor activation in the rostral ventrolateral medulla mediates the sympathoexcitatory response to hyperinsulinemia. Hypertension 55:284-90
Stocker, Sean D; Madden, Christopher J; Sved, Alan F (2010) Excess dietary salt intake alters the excitability of central sympathetic networks. Physiol Behav 100:519-24
Toney, Glenn M; Stocker, Sean D (2010) Hyperosmotic activation of CNS sympathetic drive: implications for cardiovascular disease. J Physiol 588:3375-84

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