Central Nervous System Mechanisms of Obesity Hypertension

描述(由申请人提供)：弗雷明翰心脏研究的风险估计表明，大约75%的男性高血压和65%的女性高血压主要归因于超重和肥胖。来自临床研究和动物模型的令人信服的证据表明，交感神经流出到肾脏和后肢血管的增加在肥胖性高血压的发病机制中起着关键作用。尽管体重或肥胖与交感神经系统的激活之间存在重要关系，但人们对肥胖期间交感神经流出和动脉血压持续增加的神经通路和细胞机制知之甚少。我们实验室的长期目标是确定在肥胖中增加交感神经流出和血压的神经通路和细胞机制。据推测，肥胖患者交感神经流出和血压升高的两个传入信号是高胰岛素血症和高瘦素血症。我们的工作假设是，饮食诱导的肥胖增加了循环中的胰岛素和瘦素，激活了从弓状核到下丘脑室旁核的下行电路。随后下丘脑受体的激活增加了下丘脑室旁核交感神经元的放电，从而增强了对脑干和脊髓的兴奋性驱动。这种增强的兴奋性驱动力增加了交感神经流出和动脉血压。在这项应用中，我们将使用国家或最先进的电生理学方法来确定支持肥胖性高血压的中心机制。具体目标1将确定下丘脑室旁核内高胰岛素血症和高瘦素血症增加交感神经流出的细胞机制。具体目标2将确定延髓头端腹外侧区高胰岛素血症和高瘦素血症增加交感神经流出的细胞机制。具体目标3将确定在饮食诱导肥胖的啮齿动物模型中，下丘脑室旁核和延髓头端腹外侧支持交感神经流出增加和血压升高的机制。我们这个项目的基本原理是，确定介导胰岛素和瘦素交感兴奋作用的神经通路和机制，以及这些通路如何最终导致肥胖性高血压，将为开发新的治疗方法提供框架。

DESCRIPTION (provided by applicant): 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.