Central Nervous System Mechanisms of Obesity Hypertension

描述（由申请人提供）：来自Framingham心脏研究的风险估计表明，约75%的男性原发性高血压和65%的女性原发性高血压主要归因于体重过重和肥胖。来自临床研究和动物模型的令人信服的证据表明，增加的交感神经流向肾脏和后肢血管在肥胖引起的高血压的发病机制中起关键作用。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，但对于肥胖期间交感神经流出量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肥胖患者增加交感神经流出和血压的神经通路和细胞机制。高胰岛素血症和高瘦素血症被认为是肥胖患者交感神经流出和血压升高的两种传入信号。我们的工作假设是，饮食引起的肥胖增加了循环胰岛素和瘦素，从而激活了从弓状核到下丘脑室旁核的下行回路。下丘脑随后的受体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驱动。这种增强的兴奋驱动增加了交感神经流出和动脉血压。在这个应用中，我们将使用最先进的电生理方法来确定支持肥胖诱导的高血压的中心机制。具体目的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。特异性目的2将确定高胰岛素血症和高瘦素血症增加交感神经流出的吻侧腹外侧髓质的细胞机制。具体目标3将确定下丘脑室旁核和吻侧腹外侧髓质的机制，这些机制支持饮食性肥胖啮齿动物模型中交感神经流出和血压升高。我们这个项目的基本原理是确定介导胰岛素和瘦素交感神经兴奋作用的神经通路和机制，以及这些通路最终如何促进肥胖诱导的高血压，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.