Leptin in Human Energy and Neuroendocrine Homeostasis

描述（由申请人提供）：超过50%的美国成年人超重（BMI指数为25kg / m2），并且有肥胖相关疾病的“危险”。肥胖治疗的失败，以维持体重减轻是公认的。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体重减轻的过程中发生改变，有利于体重恢复；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；和3)。因此，如果循环瘦素浓度恢复到体重减轻前的水平，伴随体重减轻的能量和神经内分泌稳态系统的变化将会逆转。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，这些变化减少了能量消耗，增加了食物摄入，其方式类似于在缺乏或抵抗脂肪细胞来源的激素瘦素的啮齿动物和人类中所看到的。对瘦素缺乏的啮齿动物和人类进行全身瘦素治疗，可逆转代谢（低代谢、嗜食）、自主神经（副交感神经系统张力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）变化，这些变化是瘦素缺乏状态的特征。拟议的研究侧重于神经内分泌、行为、自主和代谢变化，这些变化是减轻肥胖个体的特征，以及瘦素循环浓度恢复到减肥前水平对这些表型的影响。肥胖受试者将被纳入哥伦比亚大学CRC，并在1.)正常体重（初始体重），2.)维持10%体重减轻（Wt-10%）期间进行研究，3.)在维持10%体重减轻期间接受外源性瘦素，剂量足以使循环瘦素恢复到减肥前的浓度。在每个研究期间，受试者将接受详细的评估：1.)能量消耗（10天水的重同位素排泄差异，静息能量消耗的间接量热法，非静息能量消耗，喂养的热效应，体力活动时间）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（如脂联素、胃饥饿素、PYY、IL-6、IL-1Ra）。我们预测，瘦素给药将逆转代谢、自主神经和神经内分泌表型特征的体重减轻状态。这些研究结果将进一步阐明体重调节和瘦素的生理机制。

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.