Sympathetic and vascular control in genetic obesity

遗传性肥胖的交感神经和血管控制

• 批准号: 6843767
• 负责人: ALLYN L. MARK
• 金额: $ 17.58万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843767
• 关键词: blood pressure; hormone inhibitor; hormone regulation /control mechanism; hormone sensitivity /resistance; hypertension; laboratory mouse; leptin; norepinephrine; obesity; telemetry; vascular smooth muscle nervous control; weight control agent

Obesity is a leading risk for arterial hypertension. In the past fie years, there have been dramatic advances in understanding the genetics and molecular physiology of obesity with the discovery of the leptin and melanocortin systems. This proposal is designed to advance understanding of the physiologic mechanisms and role of leptin, melanocortins, and agoutin protein in regulation of sympathetic activity, vascular reactivity, and arterial pressure. To evaluate the physiologic mechanisms and role of leptin in regulation of arterial pressure, one set of studies will address these questions. 1. Does loss of a physiologic sympathetic action of leptin result in lower arterial pressure in ob mice? 2. Does leptin deficiency or resistance decrease renal norepinephrine spillover in leptin-deficient and resistant mice? 3. Does leptin deficiency or resistance decrease renal norepinephrine spillover in leptin-deficient and resistant mice? 3. Does neuropeptide Y contribute to the decreased sympathetic activity and arterial pressure in db mice? We have also recently demonstrated that agouti fellow obese mice have elevated arterial pressure. This murine model is characterized by widespread over- expression of agouti protein, an endogenous antagonist of melanocortin-4 receptors (MC4-R). Recent studies have shown both sympathetic and vascular effects of MC4-R and agouti protein. In order to explore the mechanisms underlying elevated arterial pressure in agouti mice, we will address the following questions: 1. Do obese mice lacking functional MC4-R have elevated arterial pressure. 2. Do agouti obese mice have selective leptin resistance with preservation of the sympathoexcitatory actions but loss of the peptide and weight reducing actions of leptin; and 3. What are the mechanisms underlying the direct vascular effects of agouti protein? These studies will use state-of-the-art techniques including measurement of regional norepinephrine turnover and continuous direct radiotelemetric measurement of arterial pressure in conscious unrestrained mice. This proposal promises to advance our understanding of novel mechanisms that may underlie obesity-induced alterations in arterial pressure.

肥胖是动脉高血压的主要风险。在过去的五年中，随着瘦素和黑皮质素系统的发现，对肥胖的遗传学和分子生理学的理解有了巨大的进展。这个建议的目的是促进了解的生理机制和作用的瘦素，黑皮质素，和agoutin蛋白调节交感神经活性，血管反应性和动脉压。为了评估瘦素在调节动脉压中的生理机制和作用，一组研究将解决这些问题。1.瘦素交感神经生理作用的丧失是否导致肥胖小鼠动脉压降低？2.瘦素缺乏或抵抗是否减少瘦素缺乏和抵抗小鼠的肾去甲肾上腺素溢出？3.瘦素缺乏或抵抗是否减少瘦素缺乏和抵抗小鼠的肾去甲肾上腺素溢出？3.神经肽Y是否与db小鼠交感神经活性和动脉压降低有关？我们最近也证明了肥胖小鼠的动脉压升高。该鼠模型的特征在于聚集蛋白的广泛过表达，聚集蛋白是黑皮质素-4受体（MC 4-R）的内源性拮抗剂。最近的研究表明MC 4-R和agglutinin蛋白具有交感神经和血管效应。为了探讨动脉压升高的机制，我们将解决以下问题：1。缺乏功能性MC 4-R的肥胖小鼠动脉压升高吗？2.单纯性肥胖小鼠是否存在选择性瘦素抵抗，保留了瘦素的交感兴奋作用，但丧失了瘦素的肽和减肥作用; agglutinin蛋白直接作用于血管的机制是什么？这些研究将使用最先进的技术，包括测量清醒无约束小鼠的局部去甲肾上腺素周转和动脉压的连续直接无线电遥测测量。这一提议有望促进我们对肥胖引起的动脉压改变的新机制的理解。