Neuronal Mechanisms of Obesity and Hypertension: Role of the BBSome

摘要： 肥胖症在美国已经很普遍，是高血压的主要原因， 心血管疾病的可逆风险因素。然而，这种关系背后的机制 肥胖和高血压之间的关系仍不清楚。这项提案的目标是确定神经元 以及控制能量平衡和血压的分子过程，以及这些过程中的失调 这些过程导致肥胖和肥胖相关的高血压。这项建议是根据我们最近的 工作证明了神经元Bardet Biedl综合征（BBS）蛋白在调节 能量平衡和血压。我们发现BBSome是一种由八种BBS蛋白组成的复合物， 这是神经元控制能量平衡的受体运输所必需的。我们进一步 假设下丘脑BBSome缺陷导致常见的饮食性肥胖和相关的 交感神经活动和血压增加。这一点得到了我们最近有趣的 暗示高血压高脂肪饮食诱导的肥胖小鼠中BBSome功能障碍的初步数据。 为了验证我们的假设，我们将研究恢复饮食诱导的下丘脑中的BBSome是否会影响饮食诱导的下丘脑中的BBSome。 肥胖小鼠减轻肥胖增加，能量失衡，激活大脑中的肾素-血管紧张素 系统和血压和交感神经活动的增加。我们还将确定 BBSome介导的调节能量稳态的受体运输的基础过程， 使用化学遗传学来评估由BB体破坏引起的缺陷的特异性和范围， 下丘脑神经元这些创新的研究将采用独特而复杂的遗传策略， 神经技术和生理学的方法应该解开肥胖的新机制， 肥胖相关的心血管风险，使我们的工作具有高度的临床意义。深入了解细胞 而控制能量平衡和心血管功能的分子过程可能使其成为可能， 选择性地干预肥胖对心血管功能造成的损害。

Abstract: Obesity which has become common in the United States is a major cause of hypertension, a principal reversible risk factor for cardiovascular disease. However, 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 energy homeostasis and blood pressure and how dysregulation in these processes contribute to obesity and obesity-associated hypertension. This proposal is based on our recent work demonstrating the importance of neuronal Bardet Biedl syndrome (BBS) proteins in the regulation of energy homeostasis and blood pressure. We discovered that the BBSome, a complex of eight BBS proteins, is required for the trafficking of receptors that underlie neural control of energy homeostasis. We further hypothesize that defects in the hypothalamic BBSome contribute to common dietary obesity and associated increase in sympathetic nerve activity and blood pressure. This is supported by our recent intriguing preliminary data implicating dysfunction of the BBSome in the hypertensive high fat diet-induced obese mice. To test our hypothesis, we will investigate whether restoring the BBSome in the hypothamus of diet-induced obese mice alleviate the increased adiposity, energy imbalance, activation of the brain renin-angiotensin system and the increase in blood pressure and sympathetic nerve activity. We will also determine the cellular processes underlying the BBSome-mediated trafficking of the receptors regulating energy homeostasis and use chemogenetics to assess the specificity and extend of the defects caused by disruption of the BBsome in hypothalamic neurons. These innovative studies which will employ unique and sophisticated genetic strategies, neuro-techniques and physiologic approaches should unravel novel mechanisms that underlie obesity and obesity-associated cardiovascular risks, making our work of high clinical relevance. Insights into the cellular and molecular processes that control energy balance and cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular function.