LEPTIN AND VENTILATORY CONTROL DURING SLEEP

在西方社会，肥胖症的流行正在急剧增加，特别是在美国，22%的人口的身体质量指数超过30公斤/平方米。随着体重的增加，个人可能会出现二氧化碳分压升高、静息状态下二氧化碳水平升高和高碳酸血症呼吸反应减弱(肥胖低通气症；OHS)。肥胖和呼吸抑制之间的联系机制尚不清楚。这一提议的前提是，最近克隆的代谢激素瘦素可以预防肥胖患者的呼吸抑制。我们的发现表明，缺乏循环瘦素的肥胖ob/ob小鼠表现出OHS的主要临床特征，瘦素替代逆转了独立于体重的呼吸抑制。目前的应用旨在探索瘦素对呼吸控制的影响，以及调节其作用的途径和因素。各种转基因小鼠和新技术被用来测量慢性仪器化小鼠的通气量、睡眠觉醒/状态和动脉血气。从小鼠实验中获得的洞察力将应用于人类，以确定瘦素与肥胖患者通气量之间的关系。明确目标L，研究瘦素是否可以增加中枢化学感受器的获得，以及肥胖小鼠体内脂肪急剧减少10%是否影响呼吸控制。特定目的2研究瘦素是否通过下丘脑和外周化学感受器途径改变呼吸控制。具体目标3，研究瘦素是否作为对慢性缺氧的代偿反应而上调。在具体目标4中，机制动物研究将扩展到确定严重肥胖人类中枢神经系统中的瘦素水平与PaCO2之间的关系。最后，将探讨性别和睡眠/清醒状态在具体目标1-4中的作用。这些研究将加深对肥胖症呼吸衰竭发病机制的了解，为了解瘦素在其他原因导致的呼吸衰竭患者中的作用提供洞察力，并提供特定治疗干预的可能性。

The prevalence of obesity is increasing dramatically in western society, especially in the U.S. where 22% of the population have a body mass index greater than 30 kg/m2. As weight is gained, individuals can develop elevated, resting levels of PaCO2 and depressed hypercapnic ventilatory responses (Obesity Hypoventilation Syndrome; OHS). The mechanisms that link obesity and respiratory depression are unclear. The premise of this proposal is that the recently cloned metabolic hormone, leptin, can prevent respiratory depression in obesity. Our findings indicate that obese ob/ob mice, which lack circulating leptin, exhibit the major clinical features of OHS, and that leptin replacement reverses respiratory depression independent of weight. The current application is designed to explore influences of leptin on ventilatory control, and the pathways and factors which modulate its effect. Various transgenic mice and novel techniques are employed to measure ventilation, sleep wake/state and arterial blood gases in chronically instrumented mice. Insights gained from murine experiments will be applied in humans to define the relationship between leptin and ventilation in obesity. Specific Aim l, examines whether leptin can increase the gain of central chemoreceptors, and whether an acute 10% reduction in body fat in obese mice affects ventilatory control. Specific Aim 2 examines whether leptin acts through hypothalamic and peripheral chemoreceptor pathways to alter respiratory control. Specific Aim 3, examines whether leptin is upregulated as a compensatory response to chronic hypoxia. In Specific Aim 4, the mechanistic animal studies will be extended to determine how leptin levels in the CNS relate to PaCO2 in severely obese humans. Finally, the role of gender and sleep/wake state will be explored across Specific Aims 1-4. These studies will enhance understanding of the pathogenesis of respiratory failure in obesity, provide insight into the role of leptin in patients with ventilatory insufficiency of other causes, and offer the possibility of specific therapeutic intervention.