Neuronal Mechanisms of Obesity-Induced Hypertension

退伍军人中肥胖率高是退伍军人医疗保健系统面临的主要挑战。这是 因为肥胖与交感神经流量增加有关，从而导致高血压，这是一种主要风险 导致终末器官损害、中风、心肌梗塞和充血性心力衰竭的因素。然而，蜂窝 肥胖相关心血管风险的分子病因学仍然知之甚少。我们和其他人 之前已经证明了大脑机制在肥胖病理生理学中的重要性- 诱发交感神经兴奋和高血压。瘦素的大脑活动和黑素皮质醇能系统 成为肥胖症患者交感神经流量和血压增加的主要驱动因素。研究 也揭示了雷帕霉素复合体1(MTORC1)的机制靶点在 控制交感神经活动和血压。此外，我们提供了令人信服的初步数据 证明在含有瘦素受体(LepRb)的神经元中mTORC1信号的干扰 选择性地具有提高肾交感神经活性和血压的瘦素能力。值得注意的是， LepRb神经元mTORC1的破坏对交感神经过度驱动和高血压小鼠的保护作用 在不影响体重增加和肥胖的情况下，由饮食引起的肥胖引起。此外，我们还鉴定了丝氨酸 肽酶抑制剂A3N(SerpinA3N)是mTORC1信号转导下游的一个新基因。这让我们找到了 假设LepRb神经元中的mTORC1信号和SerpinA3N介导肥胖诱导 交感神经激活和高血压。我们将通过检查转录来检验我们的假设 SerpinA3N基因的调控机制。此外，我们还将研究SerpinA3N在控制中的作用 交感神经流量、动脉压和肥胖相关高血压和交感神经 激活。我们还将剖析mTORC1中断所产生的保护作用背后的神经回路 LepRb神经元中肥胖性高血压和交感神经激活的信号。这项研究 将促进对交感神经过度驱动和高血压的潜在机制的理解 与在退伍军人管理局人群中变得普遍的肥胖有关。

The high prevalence of obesity among the veterans is a major challenge for the VA healthcare system. This is because obesity is associated with increased sympathetic nerve traffic leading to hypertension, a major risk factor for end-organ damage, stroke, myocardial infarction and congestive heart failure. However, the cellular and molecular etiology of obesity-associated cardiovascular risks remain poorly understood. We and others have previously demonstrated the importance of the brain mechanisms in the pathophysiology of obesity- induced sympathetic activation and hypertension. Brain action of leptin and the melanocortinergic system have emerged as major drivers of the increase in sympathetic nerve traffic and blood pressure in obesity. Studies from our lab also revealed the importance of the mechanistic target of rapamycin complex 1 (mTORC1) in the control of sympathetic nerve activity and blood pressure. Moreover, we provide compelling preliminary data demonstrating that disruption of mTORC1 signaling in the leptin receptor (LepRb)-containing neurons interfere selectively with the ability of leptin to increase renal sympathetic activity and blood pressure. Notably, mTORC1 disruption in the LepRb neurons protect mice from the sympathetic overdrive and hypertension evoked by diet-induced obesity without affecting weigh gain and adiposity. Moreover, we identified serine peptidase inhibitor A3N (SerpinA3N) as a novel gene downstream to mTORC1 signaling. This led us to hypothesize that mTORC1 signaling and SerpinA3N in the LepRb neurons mediate obesity-induced sympathetic nerve activation and hypertension. We will test our hypothesis by examining the transcription mechanisms that regulate SerpinA3N gene. In addition, we will investigate the role of SerpinA3N in the control of sympathetic nerve traffic, arterial pressure and obesity-associated hypertension and sympathetic nerve activation. We will also dissect the neurocircuit underlying the protection conferred by disruption of mTORC1 signaling in LepRb neurons on obesity-induced hypertension and sympathetic nerve activation. This research will advance understanding of the mechanisms underlying the sympathetic overdrive and hypertension associated with obesity that has become common in the VA population.