Leptin signaling in the carotid body: mechanisms and consequences

肥胖通过多种机制导致高心血管发病率和死亡率，包括 高血压和阻塞性睡眠呼吸暂停（OSA）的患病率和严重程度增加。我们的主要论点是， 肥胖通过增加脂肪细胞产生的激素水平而加重高血压和OSA 瘦素是交感神经系统（SNS）的有效刺激物。高瘦素血症与 高血压和过度活跃的缺氧性反应（HVR），这可能会加重合并OSA。的 OSA的进展会进一步加重高血压。我们提出了一种新的机制，瘦素的作用， 在颈动脉体（CB）外周施加SNS和HVR效应。CB主要为外周缺氧 肥胖和阻塞性睡眠呼吸暂停综合征的敏感传感器。我们的初步数据表明：（1）瘦素通过非- 选择性阳离子瞬时受体电位通道melastatin 7（TRPM 7），（2）瘦素调节HVR， 这种作用被TRPM7阻断剂消除;（3）瘦素诱导高血压，这种作用被CSN消除 （4）瘦素受体缺陷db/db小鼠CB中瘦素ObRb受体的补充增加 Trpm7表达和HVR加重睡眠呼吸暂停我们的首要假设是瘦素 增强CB化学反射，通过TRPM7通道起作用以加重OSA并诱导 高血压我们提出了一个多学科的方法，利用电生理，分子和表观遗传 技术，以及用于连续记录睡眠呼吸暂停和心血管疾病的先进技术。 CB靶向小鼠模型中的变量。具体目标1将确定瘦素的机制， 增强CB活性。我们将检查（A）瘦素信号传导是否急剧增加TRPM7通道活性， 导致CB球细胞[Ca~（2+）] i和膜去极化增加， 化学感受器反应;和（B）长时间暴露于瘦素通过以下途径慢性上调Trpm 7转录 表观遗传机制具体目标2将确定瘦素影响CB的机制 化学反射和睡眠呼吸暂停我们将研究瘦素对CB化疗反射和睡眠呼吸暂停的影响， 通过使用（A）具有CB特异性瘦素ObRb受体过表达和敲除的小鼠;和（B）具有CB特异性瘦素ObRb受体过表达和敲除的小鼠， CB特异性Trpm7基因敲除或用TRPM7抑制剂治疗。具体目标3将决定 CB中的瘦素信号传导影响血压的机制。我们将研究瘦素对 （A）在具有CB特异性ObRb过表达和敲除的小鼠中连续监测血压;（B）在具有CB特异性ObRb过表达和敲除的小鼠中连续监测血压。 CB特异性Trpm7基因敲除小鼠和用TRPM7抑制剂处理的小鼠中。该项目将有一个 通过定义CB功能和发病机制的激素调节的新概念， 高血压和睡眠呼吸暂停综合征的发病率。我们的建议的成功实施将确定新的 用于治疗高血压和睡眠呼吸暂停的治疗靶点。

Obesity leads to high cardiovascular morbidity and mortality acting via multiple mechanisms including increased prevalence and severity of hypertension and obstructive sleep apnea (OSA). Our main thesis is that obesity exacerbates hypertension and OSA acting via increased levels of an adipocyte produced hormone leptin, a potent stimulator of the sympathetic nervous system (SNS). Hyperleptinemia is associated with hypertension and overactive hypoxic ventilatory response (HVR), which may exacerbate comorbid OSA. The progression of OSA would further aggravate hypertension. We propose a novel mechanism that leptin acts peripherally on the carotid bodies (CB) to exert SNS and HVR effects. CB are major peripheral hypoxia sensors sensitized by obesity and OSA. Our preliminary data show that (1) leptin stimulates CB via non- selective cation transient receptor potential channel melastatin 7 (TRPM7), that (2) leptin regulates HVR and this effect is abolished by TRPM7 blockers; (3) leptin induces hypertension and this effect is abolished by CSN denervation; (4) replenishment of leptin ObRb receptor in CB of leptin receptor deficient db/db mice increases Trpm7 expression and HVR exacerbating sleep apnea. Our overarching hypothesis is that leptin augments the CB chemoreflex acting via TRPM7 channels to exacerbate OSA and induce hypertension. We propose a multidisciplinary approach using electrophysiological, molecular and epigenetic techniques, as well as advance techniques for continuous recording of sleep apnea and cardiovascular variables in CB-targeted mouse models. Specific Aim 1 will determine the mechanisms by which leptin augments CB activity. We will examine whether (A) leptin signaling acutely increases TRPM7 channel activity, leading to increase in [Ca2+]i and membrane depolarization in the CB glomus cells and augmenting CB chemoreceptor response; and (B) prolonged exposure to leptin chronically upregulates Trpm7 transcription via epigenetic mechanisms. Specific Aim 2 will determine the mechanisms by which leptin affects the CB chemoreflex and sleep apnea. We will examine the effects of leptin on CB chemo reflex and sleep apnea in mice by using (A) mice with CB specific leptin ObRb receptor overexpression and knockout; and (B) mice with CB specific Trpm7 gene knockout or treated with TRPM7 inhibitors. Specific Aim 3 will determine the mechanisms by which leptin signaling in CB affects blood pressure. We will examine the effects of leptin on continuously monitored blood pressure (A) in mice with CB specific ObRb overexpression and knockout; (B) in mice with CB specific Trpm7 gene knockout and in mice treated with TRPM7 inhibitors. This project will have a significant impact by defining a novel concept of hormonal regulation of the CB functions and the pathogenesis of hypertension and sleep apnea in obesity. The successful implementation of our proposal will identify novel therapeutic targets for the treatment of hypertension and sleep apnea.