Impaired Brain-Leptin Interaction in Chronic Tobacco Us*

慢性吸烟者大脑与瘦素相互作用受损*

基本信息

批准号：
6594124
负责人：
YIJUN LIU
金额：
$ 21.28万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2004-09-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Smoking cessation may result in considerable body-weight gain, which often causes relapse or deters smokers from quitting. While leptin plays a key role in the control of body-weight, plasma leptin levels in cigarette smokers are significantly higher than those in non-smokers. Although cigarette smoking produces acute behavioral effects, its chronic effects on the central nervous system (CNS), which are associated with psychophysiological functions and neuroendocrinal changes, have not been investigated using neuroimaging. This may be partially due to the lack of suitable in vivo human models for directly examining the brain activity that is responsible for the regulation of those changes (e.g., biochemical signals such as the circulating insulin and leptin). The objective of this proposed project is to characterize brain activity that is associated with plasma leptin levels in chronic tobacco users. Specifically, we will use functional magnetic resonance imaging (fMRI) to compare the timing and localization of neural-hormonal interaction following food intake between smokers and non-smokers, with the focuses on the hypothalamus and its associated brain circuits using a novel dynamic approach developed by the PI. It is still not clear how leptin is regulated in the human brain; and much less is known about the interrelationship between peripheral leptin levels and the central anorexic signaling pathways. Thus, this proposed project may provide insight into the mechanisms relating chronic smoking to leptin, and the consequence of altered brain-leptin interaction in tobacco users. Two specific aims are to be accomplished. Aim 1: To test the hypothesis that tobacco smoking is associated with central leptin regulatory pathways localized in the hypothalamus, and this functional regulatory mechanism may be impaired in chronic cigarette smokers. We will tailor a fasting-eating fMRI paradigm to characterize the brain activity that is associated with plasma leptin and insulin during eating. Specifically, we will analyze the hypothalamic fMRI signal during a real-time transition from fasting hypoglycemia to normoglycemia attained by glucose ingestion so as to determine the impairment of brain-leptin interaction in chronic cigarette smokers. In the analysis, the leptin-associated brain activities will be compared among nonsmokers and chronic smokers (with and without cessation) by controlling for body weight, the post-cessation weight gain and relapse (for subjects with cessation), and other factors such as blood pressure and cholesterol. Aim 2: To test the hypothesis that leptin may modulate the activity among hedonic and rewarding brain circuits during the control of satiety signaling, and this modulation may be affected by tobacco smoking even when anorectic effects are reinforced. We will model the central anorectic signaling pathways involving leptin and insulin in chronic tobacco users, with a focus on the hypothalamic regions and their associated brain circuits involving the medial prefrontal cortex (including the orbitofrontal cortex), the insula, and the basal ganglia. The neural modeling will be accomplished by the task-dependent interregional covariance analysis of fMRI signal in fasting subjects (smokers and controls) during exposure to food-related emotional stimuli before and after eating.

描述（由申请人提供）：戒烟可能导致体重显着增加，这通常会导致复吸或阻止吸烟者戒烟。虽然瘦素在控制体重方面发挥着关键作用，但吸烟者的血浆瘦素水平明显高于不吸烟者。尽管吸烟会产生急性行为影响，但其对中枢神经系统（CNS）的慢性影响与心理生理功能和神经内分泌变化有关，尚未使用神经影像学进行研究。这可能部分是由于缺乏合适的体内人体模型来直接检查负责调节这些变化的大脑活动（例如，循环胰岛素和瘦素等生化信号）。该拟议项目的目标是表征长期吸烟者与血浆瘦素水平相关的大脑活动。具体来说，我们将使用功能磁共振成像（fMRI）来比较吸烟者和非吸烟者摄入食物后神经激素相互作用的时间和定位，重点是使用开发的新型动态方法来观察下丘脑及其相关的大脑回路由 PI 提供。目前尚不清楚瘦素在人脑中是如何调节的；对于外周瘦素水平与中枢厌食信号通路之间的相互关系知之甚少。因此，这个拟议的项目可以深入了解慢性吸烟与瘦素的相关机制，以及烟草使用者中大脑与瘦素相互作用改变的后果。有两个具体目标需要实现。目标 1：检验吸烟与位于下丘脑的中枢瘦素调节途径相关的假设，并且这种功能性调节机制可能在长期吸烟者中受损。我们将定制一个空腹功能磁共振成像范例来表征进食期间与血浆瘦素和胰岛素相关的大脑活动。具体来说，我们将分析从空腹低血糖到通过葡萄糖摄入达到正常血糖的实时转变过程中的下丘脑功能磁共振成像信号，以确定长期吸烟者脑-瘦素相互作用的损害。在分析中，将通过控制体重、戒烟后体重增加和复吸（对于戒烟受试者）以及其他因素（例如，血压和胆固醇。目标 2：检验瘦素可能在饱腹感信号控制过程中调节享乐和奖励大脑回路之间的活动的假设，并且即使厌食效应增强，这种调节也可能受到吸烟的影响。我们将模拟长期吸烟者中涉及瘦素和胰岛素的中枢厌食信号通路，重点关注下丘脑区域及其相关的大脑回路，涉及内侧前额皮质（包括眶额皮质）、岛叶和基底神经节。神经建模将通过对禁食受试者（吸烟者和对照组）在进食前后暴露于食物相关情绪刺激期间的 fMRI 信号进行任务依赖性区域间协方差分析来完成。