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

项目总结/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。 肥胖症在美国和全世界都很常见，是高血压的主要原因， 肥胖和高血压之间的关系的潜在机制在很大程度上仍不清楚。的 这项计划的目标是确定控制血压的神经元和分子过程，以及如何控制血压。 这些过程中的失调导致肥胖相关的心血管风险。该提案基于 假设肥胖诱导的激素成纤维细胞生长因子21（FGF 21）的升高促进了 通过激活表达类固醇生成因子1（SF 1）的下丘脑腹内侧神经元， 增加交感神经活动。我们将采用多学科策略结合尖端神经- 技术，以精确和远程调制或监测SF 1神经元的活动， 具有允许选择性调节FGF 21信号传导的独特基因工程小鼠模型的动物 在SF 1神经元和复杂的综合生理交感神经和心血管表型。我们 计划通过确定化学遗传学或光遗传学介导的激活或激活如何来测试我们的中心假设 在正常情况下，抑制SF 1神经元活性影响交感神经流出和动脉压， 肥胖症也是如此。我们还将探讨FGF 21信号在下丘脑腹内侧区的作用。 包括SF 1神经元对交感神经和动脉压的控制以及肥胖相关的高血压， 交感神经激活这项工作应该揭示肥胖相关的新机制， 交感神经激活和高血压，使我们的工作具有高度的临床意义。深入了解细胞 而控制交感神经张力的分子过程可能会调节心血管功能， 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.