Role of Leptin in the Neuroendocrine Response to Fasting

瘦素在禁食神经内分泌反应中的作用

基本信息

批准号：
6781763
负责人：
CHRISTOS S MANTZOROS
金额：
$ 47.68万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-15 至 2005-09-14
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Over the last several years, an explosion of data on the role of distinct peptides in regulating food intake and energy expenditure has fundamentally altered our understanding of regulation of body weight and energy expenditure and has broadened significantly our view of the potential molecular mechanisms underlying the pathogenesis and clinical manifestations of eating disorders, including obesity and anorexia nervosa. Central to these observations was the discovery of leptin which plays a central role in signaling the amount of energy stored in adipose tissue to the central nervous system. In addition to its role in obesity, our laboratory has explored two additional central roles of leptin, i.e. the role of leptin in regulating immune function and in mediating the neuroendocrine response to states of caloric deprivation in rodents. The current proposal will provide a transition from our laboratory observations to studies in normal human volunteers. Thus, we will study the physiology of leptin's secretion in lean and obese subjects and we will investigate the potential role of leptin as a regulator of energy expenditure and immune function and as mediator of the neuroendocrine response to food deprivation in humans. We hypothesize that 1) A fall in leptin blood levels and/or a change in its pattern of secretion in response to food deprivation are associated with the food deprivation-induced neuroendocrine and/or immune changes in humans, 2) Leptin administration to fasted humans will ameliorate the immune and/or neuroendocrine changes associated with food deprivation and 3) There are differences in leptin's role between men and women as well as lean and obese subjects. To examine these three hypotheses, we will measure energy expenditure and immune function and we will perform frequent blood sampling (every 15 min.) for 24 hours to assess hypothalamic-pituitary-end organ axes in a total of 32 subjects: 8 lean men, 8 lean women, 8 obese men and 8 obese women. Subjects will be studied under three conditions: a) Baseline, i.e. normal food consumption with placebo subcutaneous injections b) Following 3 days of food deprivation with placebo leptin subcutaneous injections, and c) Following 3 days of food deprivation with recombinant human leptin subcutaneous injections (The order of b and c will be randomized and double-blind). Data derived from these studies will increase our understanding of the normal physiology of leptin and its role in regulating energy expenditure, neuroendocrine and immune response in the fed and fasted states in normal humans, In addition, these data will provide important insights into the neuroendocrine response to therapeutic dieting in obesity and elucidate the pathophysiology of the neuroendocrine changes seen in anorexia nervosa and may also provide the basis for future therapeutic interventions for obesity and anorexia nervosa.

描述（由申请人提供）：在过去的几年中，爆炸关于不同肽在调节食物摄入和能量的作用的数据支出从根本上改变了我们对身体调节的理解体重和能源消耗，并大大扩大了我们对发病机理和临床的潜在分子机制饮食失调的表现，包括肥胖和神经性厌食症。这些观察结果的中心是发现瘦素的发现在信号脂肪组织中存储到中心的能量的作用神经系统。除了在肥胖中的作用外，我们的实验室还探索了瘦素的另外两个核心作用，即瘦素在调节中的作用免疫功能并介导神经内分泌的反应啮齿动物的热量剥夺。当前的建议将提供过渡从我们的实验室观察到正常人类志愿者的研究。因此，我们将研究瘦素和肥胖学科中瘦素分泌的生理学我们将研究瘦素作为能量调节剂的潜在作用支出和免疫功能，作为神经内分泌反应的中介在人类中剥夺食物。我们假设1）瘦素血液下降对食物的分泌模式的水平和/或变化剥夺与食物剥夺引起的神经内分泌有关和/或人类的免疫变化，2）对禁食人的瘦素给药将改善与食物相关的免疫和/或神经内分泌变化剥夺和3）男性和女性的瘦素角色存在差异以及精益和肥胖的主题。为了审查这三个假设，我们将测量能量消耗和免疫功能，我们将频繁执行抽血（每15分钟一次）24小时评估下丘脑 - 垂体 - 末端器官轴总共32个受试者：8个瘦男人，8个精益妇女，8名肥胖男性和8个肥胖女人。主题将在三个下进行研究条件：a）基线，即安慰剂皮下的正常食物消耗注射b）在3天的食物剥夺后，安慰剂瘦素皮下注射，c）剥夺食物后3天重组人瘦素皮下注射（B和C的顺序将是随机和双盲）。这些研究得出的数据将增加我们的了解瘦素的正常生理及其在调节中的作用美联储和禁食的能量消耗，神经内分泌和免疫反应另外，正常人中的状态还将提供重要的对肥胖症中神经内分泌对治疗饮食的反应的见解阐明厌食症中神经内分泌变化的病理生理学神经，还可能为将来的治疗干预措施提供基础肥胖和神经性厌食症。