Role of FGF21 Action in Hypothalamic Neurons in Obesity-Associated Hypertension

项目摘要/摘要 高血压影响着10亿人，是心血管疾病的主要可逆风险因素。 肥胖在美国和全世界都很常见，是高血压的主要原因，但 肥胖症和高血压之间关系的潜在机制在很大程度上仍不清楚。这个 这项提议的目标是确定控制血压的神经元和分子过程以及如何 这些过程中的失调会导致肥胖相关的心血管风险。这项建议是基于 关于肥胖诱导激素成纤维细胞生长因子21(FGF21)升高促进的假说 激活表达类固醇生成因子1的下丘脑腹内侧神经元引起的高血压 增强交感神经活性。我们将使用多学科策略结合尖端神经学- 精确和远程调节或监测自由运动中SF1神经元活动的技术 具有独特的基因工程小鼠模型的动物，允许选择性地调节FGF21信号 在SF1神经元和复杂的交感和心血管表型综合生理学。我们 计划通过确定化学发生或光遗传介导的激活或 抑制SF1神经元的活动在正常情况下会影响交感神经流出和动脉压 在肥胖方面也是如此。我们还将探讨FGF21信号在下丘脑腹内侧的作用 包括SF1神经元对交感神经和动脉压控制以及肥胖相关高血压和 交感神经激活。这项工作应该会揭开肥胖相关的新机制 交感神经的激活和高血压，使得我们的工作具有很高的临床意义。对蜂窝网络的洞察 控制交感神经张力调节心血管功能的分子过程可能会使 有可能选择性地干预肥胖对心血管交感神经功能造成的损害。

Project Summary / Abstract Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Obesity which has become common in the US and throughout the world is a major cause of hypertension, but the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control blood pressure and how dysregulation in these processes contribute to obesity-associated cardiovascular risks. This proposal is based on the hypothesis that obesity-induced elevation in the hormone fibroblast growth factor 21 (FGF21) promotes hypertension by activating ventromedial hypothalamic neurons expressing steroidogenic factor 1 (SF1) to increase sympathetic nerve activity. We will use a multidisciplinary strategy combining cutting edge neuro- technologies to precisely and remotely modulate or monitor the activity of SF1 neurons in freely moving animals with unique genetically engineered mouse models that permit selective modulation of FGF21 signaling in SF1 neurons and sophisticated integrative physiology for sympathetic and cardiovascular phenotyping. We plan to test our central hypothesis by determining how chemogenetic- or optogenetic-mediated activation or inhibition of SF1 neuron activity affects sympathetic outflow and arterial pressure under normal conditions as well as in obesity. We will also explore the contribution of FGF21 signaling in ventromedial hypothalamus including SF1 neurons to sympathetic and arterial pressure control and obesity-associated hypertension and sympathetic nerve activation. This work should unravel novel mechanisms that underlie obesity-associated sympathetic activation and hypertension, making our work of high clinical relevance. Insights into the cellular and molecular processes that control the sympathetic tone that regulates cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular sympathetic functions.