Neuronal Mechanisms of Obesity-Induced Hypertension

退伍军人中肥胖症的高发率是退伍军人管理局医疗保健系统面临的一个重大挑战。这是 因为肥胖与交感神经交通增加有关，导致高血压， 终末器官损伤、中风、心肌梗死和充血性心力衰竭的因素。然而，Cellular 和肥胖相关的心血管风险的分子病因学仍然知之甚少。我们和其他人 先前已经证明了大脑机制在肥胖症病理生理学中的重要性- 诱发交感神经激活和高血压。瘦素和黑素皮质素能系统的脑作用 成为肥胖患者交感神经交通和血压增加的主要驱动因素。研究 我们实验室的研究还揭示了雷帕霉素复合物1（mTORC 1）的机制靶点在肿瘤中的重要性。 控制交感神经活动和血压。此外，我们还提供了令人信服的初步数据， 这表明在含有瘦素受体（LepRb）的神经元中破坏mTORC1信号传导干扰 选择性地与瘦素增加肾交感神经活性和血压的能力。值得注意的是， LepRb神经元中mTORC 1的破坏保护小鼠免受交感神经损伤和高血压 诱发的饮食引起的肥胖，而不影响体重增加和肥胖。此外，我们发现丝氨酸 peptidase inhibitor A3N（SerpinA3N）作为mTORC 1信号转导下游的新基因。这导致我们 假设LepRb神经元中的mTORC 1信号传导和SerpinA3N介导肥胖诱导的 交感神经激活和高血压。我们将通过检查转录来验证我们的假设 SerpinA3N基因的调控机制。此外，我们还将研究SerpinA3N在对照组中的作用。 交感神经交通，动脉压和肥胖相关的高血压和交感神经 activation.我们还将解剖mTORC1破坏所提供的保护的神经回路 肥胖诱导的高血压和交感神经激活中LepRb神经元的信号传导。本研究 将促进对交感神经兴奋和高血压机制的理解 在退伍军人管理局人群中已经很常见了。

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.