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: 6671285
• 负责人: RUDOLPH L LEIBEL
• 金额: $ 38.77万
• 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/6671285
• 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%的美国成年人超重(BMI&GT；25公斤/平方米)，并有肥胖相关疾病的风险。人们普遍认识到，肥胖治疗未能持续减轻体重。这些研究的中心假设是：1.)能量和神经内分泌稳态系统在保持体重减轻的过程中会发生改变，从而有利于体重恢复；这些变化的发生是因为体重减轻的人由于身体脂肪的减少而处于相对瘦素缺乏的状态；以及因此，如果循环中的瘦素浓度恢复到减肥前的水平，那么伴随着减轻体重的维持的能量和神经内分泌平衡系统的这些变化将被逆转。保持体重减轻与综合自主神经和神经内分泌变化有关，这些变化减少了能量消耗，增加了食物摄入量，其方式类似于缺乏或抵抗脂肪细胞衍生荷尔蒙瘦素的啮齿动物和人类。对于瘦素缺乏的啮齿类动物和人类，全身应用瘦素可以逆转代谢(代谢低下、吞噬功能亢进)、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-肾上腺轴活性增加，下丘脑-垂体-甲状腺和性腺轴活性降低)的变化，这些变化是瘦素缺乏状态的特征。拟议的研究集中在神经内分泌、行为、自主神经和代谢的变化，这些变化是减肥者的特征，以及将循环瘦素浓度恢复到减肥前的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岁时学习。)通常体重(WtInitial)，2。在保持体重减轻10%(Wt-10%)的过程中，以及3.在体重减轻10%的维持期间，以足够的剂量接受外源性瘦素，以使循环中的瘦素恢复到减肥前的浓度。在每个研究阶段，受试者都将接受详细的评估。)能量消耗(10天水中重同位素的不同排泄，静息能量消耗的间接量热法，非静息能量消耗，摄食的热效应，体力活动时间)和食欲行为(饥饿和饱腹感的评估)；自主神经系统张力(连续阻断交感和副交感传入、心率变异性分析和尿儿茶酚胺排泄)；下丘脑-垂体-甲状腺，-肾上腺和-性腺，轴功能；脂肪组织基因表达；其他可能影响神经内分泌和代谢功能的分子(如脂联素、Ghrelin、PYY、IL-6、IL-1ra)。我们预测，瘦素的应用将逆转以减轻体重状态为特征的代谢、自主神经和神经内分泌表型。这些研究的结果将进一步描绘体重调节和瘦素的生理学。