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: 7056225
• 负责人: RUDOLPH L LEIBEL
• 金额: $ 35.46万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056225
• 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> 25 kg/m 2）和与肥胖相关的病态的“风险”。肥胖治疗无法维持体重减轻的失败被广泛认可。这些研究的中心假设是：1。）能量和神经内分泌稳态系统在维持减轻体重减轻的过程中会改变，从而有利于减轻体重的恢复； 2.）发生这些变化是因为减轻体重的个体由于体内脂肪损失而处于相对瘦素缺乏状态； 3.）因此，如果循环瘦素浓度恢复到减轻体重减轻的人，则这些变化的能量和神经内分泌稳态系统伴随减轻体重的维持，将会逆转。维持体重减轻与综合自主神经和神经内分泌的变化有关，这些变化减少能量消耗并增加食物摄入的方式与啮齿动物和人类相似的方式相似，这些啮齿动物和人类对脂肪细胞衍生的激素瘦素的缺乏或抗性。全身性瘦素给予瘦素缺乏啮齿动物和人类逆转代谢（多余代谢，心晶状体），自主神经（副交感神经和交感神经系统降低）和神经内分泌的降低以及神经内分泌（增加的增加（下丘脑 - 肾上腺素 - 肾上腺 - 肾上腺 - 肾上腺轴的活性），降低了特征性的邻坐核 - 下型 - 下型 - 下型 - 下型 - 下的既定型 - 下的既定型 - 瘦素缺陷状态。拟议的研究集中于表征降低肥胖个体的神经内分泌，行为，自主和代谢变化，以及对这些循环浓度的瘦素恢复到体重减轻之前存在水平的影响。肥胖的受试者将被录取为哥伦比亚大学CRC，并以1为1.）在维持体重减轻10％（WT-10％）和3.）期间接受体重（Wtinitial）。在每个研究期间，受试者将对1.）进行详细评估（10天的差分排泄，对水的大同位素，间接的量热法，用于静止能量消耗，非固定能量消耗，非遗传能量消耗，不恢复能量消耗，喂食的热量，在喂食中花费的时间，在物理活动中花费的时间）和开胃菜（评估匈奴和六个猎人）； 2.）自主神经系统音调（交感神经和副交感神经输入，心率变异性分析和尿液儿茶酚胺排泄的串行阻塞）； 3.）下丘脑 - 垂体 - 甲状腺， - 肾上腺和 - 脊椎，轴功能； 4.）脂肪组织基因表达； 5.）可能影响神经内分泌和代谢功能的其他分子（例如，脂联素，生长素蛋白，PYY，IL-6，IL-1RA）。我们预测，瘦素的给药将逆转代表体重减少态的代谢，自主和神经内分泌表型。这些研究的结果将进一步描述体重调节和瘦素的生理。