Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity

项目总结： 肥胖的存在增加了患高血压和糖尿病的风险，部分原因是 胰岛素抵抗。肥胖还与交感神经激活和我们的总体假设有关 交感神经的激活与胰岛素抵抗的血管受损有关 新陈代谢活动。我们的初步研究表明：1)血压可以通过自主神经来正常化 阻断肥胖高血压患者，2)交感神经激活不提供代谢益处，因为 与肥胖相关的静息能量消耗的增加是由于脱脂质量的增加 而不是交感神经的激活。相反，自主神经阻断：3)改善胰岛素敏感性 肥胖的高血压患者，4)逆转他们受损的NO介导的扩张，以及5)降低血浆 异前列腺素，氧化应激的一种衡量标准。此外，这些异常在 负反馈循环，由此炎症/氧化应激损害一氧化氮机制， 这反过来又减少了胰岛素介导的血管扩张，这对底物输送是重要的，从而有助于 胰岛素抵抗；胰岛素抵抗导致胰岛素水平的代偿性增加，这有助于 进一步的交感神经激活。 目前的治疗指南没有专门针对肥胖性高血压的治疗，而是 不要把交感神经激活作为一线方法。因此，重要的是要确定是否或 不针对交感神经激活在治疗肥胖性高血压方面具有独特的优势 目前的方法。我们提出了一项概念验证机制研究，比较了代谢、血管、 交感神经抑制、钙通道阻滞剂和血管紧张素受体的抗炎作用 阻断肥胖高血压的治疗。我们将测试以下假设：交感神经激活有助于1) 代谢性胰岛素抵抗，损害内源性葡萄糖生成的抑制和 刺激通常由胰岛素提供的葡萄糖摄取，2)血管胰岛素抵抗，这会损害 胰岛素介导的血管扩张和微血管募集，通常促进葡萄糖摄取，以及3) 炎症和氧化应激，导致胰岛素抵抗和高血压。 拟议中的研究将评估交感神经激活对心血管系统的贡献。 和肥胖的代谢并发症，并提供了机械洞察力来确定我们是否 应该促进目前正在进行的努力，以开发针对交感神经的新疗法 激活治疗高血压。

Project Summary: The presence of obesity increases the risk for hypertension and diabetes, in part due to the development of insulin resistance. Obesity is also associated with sympathetic activation and our overarching hypothesis is that sympathetic activation contributes to insulin resistance with impairment of its vascular and metabolic actions. Our preliminary studies suggest that 1) Blood pressure can be normalized by autonomic blockade in obese hypertensives, 2) Sympathetic activation provides no metabolic benefit because the increase in resting energy expenditure associated with obesity is due to an increase in fat free mass rather than sympathetic activation. On the contrary, autonomic blockade: 3) Improves insulin sensitivity in obese hypertensives, 4) Reverses their impaired NO-mediated dilation, and 5) Reduces plasma isoprostanes, a measure of oxidative stress. Furthermore, these abnormalities are interrelated in negative feedback loops, whereby inflammation/oxidative stress impairs nitric oxide mechanisms, which in turn reduces insulin-mediated vasodilation important for substrate delivery, thus contributing to insulin resistance; insulin resistance leads to compensatory increases in insulin levels, which contributes to further sympathetic activation. Current treatment guidelines do not specifically address the treatment of obesity hypertension, and do not target sympathetic activation as a first line approach. It is important, therefore, to determine whether or not targeting sympathetic activation offers unique advantages in the treatment of obesity hypertension over current approaches. We propose a proof-of-concept mechanistic study comparing the metabolic, vascular, and anti-inflammatory effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor blockade in obesity hypertension. We will test the hypotheses that sympathetic activation contributes to 1) metabolic insulin resistance, which impairs the suppression of endogenous glucose production and the stimulation of glucose uptake normally provided by insulin, 2) vascular insulin resistance, which impairs insulin-mediated vasodilation and microvascular recruitment that normally promote glucose uptake, and 3) inflammation and oxidative stress, which contribute to insulin resistance and hypertension. The proposed studies will gauge the contribution of sympathetic activation to the cardiovascular and metabolic complications of obesity, and provide the mechanistic insight to determine whether or not we should foster the efforts currently under way to develop novel therapies targeting sympathetic activation for hypertension.