Leptin in Human Energy and Neuroendocrine Homeostasis

瘦素在人体能量和神经内分泌稳态中的作用

• 批准号: 6912559
• 负责人: RUDOLPH L LEIBEL
• 金额: $ 36.32万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912559
• 关键词: autonomic nervous system; bioenergetics; body physical activity; calorimetry; clinical research; homeostasis; hormone regulation /control mechanism; human subject; hypothalamic pituitary adrenal axis; leptin; neuroendocrine system; obesity; patient oriented research; pituitary gonadal axis; pituitary thyroid axis; satiations; weight control

DESCRIPTION (provided by applicant): Over 50% of U.S. adults are overweight (BMI > 25 kg/m 2) and "at-risk" for adiposity-related morbidities. The failure of obesity treatments to sustain weight reduction is widely recognized. The central hypotheses of these studies are that: 1.) Energy and neuroendocrine homeostastic systems are altered during the maintenance of a reduced body weight in a manner that favors the regain of lost weight; 2.) These changes occur because weight-reduced individuals are in a state of relative leptin deficiency due to loss of body fat; and 3.) Therefore these changes energy and neuroendocrine homeostatic systems accompanying the maintenance of a reduced body weight will be reversed if circulating leptin concentrations are restored to those that were present prior to weight reduction. Maintenance of a reduced body weight is associated with integrated autonomic and neuroendocrine changes that reduce energy expenditure and increase food intake in a manner that is similar to that seen in rodents and humans who are deficient in, or resistant to, the adipocyte-derived hormone leptin. Systemic leptin administration to leptin-deficient rodents and humans reverses the metabolic (hypometabolism, hyperphagia), autonomic (increased parasympathetic and decreased sympathetic nervous system tone), and neuroendocrine (increased hypothalamic-pituitary-adrenal axis activity, decreased hypothalamic-pituitary -thyroidal and -gonadal axis activity) changes that characterize the leptin-deficient state. The proposed studies focus on the neuroendocrine, behavioral, autonomic, and metabolic changes that characterize the reduced-obese individual, and the effects on these phenotypes of restoration of circulating concentrations of leptin to levels present prior to weight loss. Obese subjects will be admitted to the Columbia University CRC and studied at 1.) usual body weight (Wtinitial), 2.) during maintenance of a 10% reduced body weight (Wt-10%), and 3.) during maintenance of a 10% reduced body weight receiving exogenous leptin at doses sufficient to restore circulating leptin to concentrations present prior to weight loss. During each of these study periods, subjects will undergo detailed evaluation of 1.) energy expenditure (10 day differential excretion of heavy isotopes of water, indirect calorimetry for resting energy expenditure, non-resting energy expenditure, and thermic effect of feeding, time spent in physical activity) and appetitive behavior (assessment of hunger and satiety); 2.) autonomic nervous system tone (serial blockade of sympathetic and parasympathetic inputs, heart rate variability analyses, and urinary catecholamine excretion); 3.) hypothalamic-pituitary -thyroid, -adrenal and -gonadal, axis function; 4.) adipose tissue gene expression; 5.) other molecules (e.g., adiponectin, ghrelin, PYY, IL-6, IL-1Ra) that may influence neuroendocrine and metabolic function. We predict that leptin administration will reverse the metabolic, autonomic, and neuroendocrine phenotypes characterizing the weight-reduced state. The results of these studies will further delineate the physiology of body weight regulation and of leptin.

描述（由申请人提供）：超过 50% 的美国成年人体重超重（BMI > 25 kg/m 2）并且有患肥胖相关疾病的“风险”。人们普遍认识到肥胖治疗无法维持体重减轻。这些研究的中心假设是： 1.) 在维持体重减轻的过程中，能量和神经内分泌稳态系统发生改变，有利于恢复减重； 2.) 这些变化的发生是因为体重减轻的个体由于体内脂肪的减少而处于相对瘦素缺乏的状态； 3.) 因此，如果循环瘦素浓度恢复到体重减轻之前的水平，则伴随体重减轻而发生的能量和神经内分泌稳态系统的这些变化将被逆转。体重减轻的维持与自主神经和神经内分泌的综合变化有关，这种变化会减少能量消耗并增加食物摄入量，其方式类似于在脂肪细胞来源的激素瘦素缺乏或抵抗的啮齿动物和人类中所见。对缺乏瘦素的啮齿动物和人类进行全身性瘦素注射，可以逆转代谢（代谢减退、食欲亢进）、自主神经（副交感神经增加和交感神经系统张力降低）和神经内分泌（下丘脑-垂体-肾上腺轴活动增加，下丘脑-垂体-甲状腺轴和性腺轴活动减少）的变化，这些变化是瘦素缺陷的啮齿动物和人类的特点。 瘦素缺乏状态。拟议的研究重点关注减重个体的神经内分泌、行为、自主和代谢变化，以及瘦素循环浓度恢复至减肥前水平对这些表型的影响。肥胖受试者将被哥伦比亚大学 CRC 录取，并在 1.) 正常体重 (Wtinitial)、2.) 维持体重减轻 10% 期间 (Wt-10%) 和 3.) 维持体重减轻 10% 期间接受外源瘦素进行研究，剂量足以将循环瘦素恢复至体重减轻前的浓度。在每个研究期间，受试者将接受以下方面的详细评估： 1.) 能量消耗（水重同位素的 10 天差异排泄、静息能量消耗的间接量热法、非静息能量消耗、进食的热效应、体力活动所花费的时间）和食欲行为（饥饿和饱腹感评估）； 2.) 自主神经系统张力（交感神经和副交感神经输入的连续阻断、心率变异性分析和尿儿茶酚胺排泄）； 3.) 下丘脑-垂体-甲状腺、-肾上腺和-性腺、轴功能； 4.) 脂肪组织基因表达； 5.) 其他可能影响神经内分泌和代谢功能的分子（例如脂联素、生长素释放肽、PYY、IL-6、IL-1Ra）。我们预测瘦素给药将逆转体重减轻状态的代谢、自主神经和神经内分泌表型。这些研究的结果将进一步描述体重调节和瘦素的生理学。