Leptin in Human Energy and Neuroendocrine Homeostasis

描述（由申请人提供）：即使是适度的体重减轻也对肥胖的合并症具有有益的影响。然而，长期保持体重减轻是罕见的。我们的中心假设是，调节体脂储存的分子生理学旨在将这些储存维持在由遗传和其他因素决定的最低水平以上。能量储存减少到这个阈值以下会引起食物摄入和能量消耗的补偿反应，其功能是恢复身体脂肪。触发这些CNS介导的变化的主要信号是脂肪细胞衍生的激素，瘦素。我们已经表明，在从不肥胖和肥胖的人中，维持体重减少10%或更多导致能量消耗减少，这主要是由于骨骼肌工作效率增加和饥饿感增加，这两者协调作用以促进身体能量储存的恢复。我们还表明，这些变化中的许多是正常的外源性瘦素的剂量足以恢复瘦素的循环浓度之前存在的体重减轻。拟议的研究重点是：具体目标#1，减重状态的体内神经/行为生物学;具体目标#2，相同减重受试者中骨骼肌工作效率增加的分子生理学。在正常体重下，体重减轻10%后，以及体重减轻加激素替代（使用瘦素或T3），肥胖和非肥胖受试者（生活在临床研究中心）将通过功能磁共振成像进行身体组成、划分的能量消耗摄取行为、自主神经系统活动、与能量摄入相关的区域神经元活动的定量研究，通过体内和体外方法对CSF进行神经肽/神经递质和代谢物的化学分析，甲状腺和肾上腺轴的功能性神经内分泌状态，骨骼肌的化学机械功能。 公共卫生相关性：肥胖现在可能是美国最大的（而且还在不断增长的）健康问题，这反映在受影响的成年人和儿童的数量上，以及对糖尿病和心血管疾病等重大、昂贵疾病的贡献上。体重调节生物学的一个主要方面是身体捍卫其脂肪含量的韧性，通过降低能量消耗和增加饥饿来补偿脂肪损失，从而导致体重恢复。拟议研究的目标是充分了解相关生物学，以便能够修改或防止这种补偿，从而能够成功维持治疗性体重减轻。

DESCRIPTION (provided by applicant): Even modest amounts of weight reduction have beneficial impact on the co-morbidities of obesity. However, long term maintenance of reduced body weight is rare. Our central hypothesis is that the molecular physiology of the regulation of body fat stores is designed to maintain these stores above a minimal level that is determined by genetic and other factors. Reduction of energy stores below this threshold invokes compensatory responses in food intake and energy expenditure that function to restore body fat. A primary signal that triggers these CNS-mediated changes is the adipocyte- derived hormone, leptin. We have shown that in both never-obese and obese humans, maintenance of a 10% or greater reduction in body weight results in reduced energy expenditure due primarily to increased skeletal muscle work efficiency and increased hunger that act coordinately to promote restoration of body energy stores. We have also shown that many of these changes are normalized by administration of exogenous leptin in doses sufficient to restore circulating concentrations of leptin to those present prior to weight loss. The proposed studies focus on: Specific Aim #1, the in vivo neuro/behavioral biology of the weight-reduced state; and Specific Aim #2, the molecular physiology of the increased skeletal muscle work efficiency in the same weight-reduced subjects. At usual body weight, following a 10% weight reduction, and at reduced weight plus hormone replacement ( with leptin or T3), obese and non-obese subjects (living in a clinical research center) will undergo quantitative studies of body composition, compartmentalized energy expenditure ingestive behavior, autonomic nervous system activity, regional neuronal activity related to energy intake by fMRI, chemical analysis of CSF for neuropeptides/neurotransmitters and metabolites, functional neuroendocrine status of thyroid and adrenal axes, chemo-mechanical function in skeletal muscle by in vivo and in vitro methods. PUBLIC HEALTH RELEVANCE: Obesity now constitutes perhaps the single greatest (and growing) health problem in the U.S. as reflected in numbers of affected adults and children, and contribution to major, costly illnesses such as diabetes and cardiovascular disease. A major aspect of the biology of weight regulation is the tenacity with which the body defends its fat content, compensating for fat loss by lowering energy expenditure and increasing hunger, leading thereby to regain of lost weight. The goal of the proposed studies is to understand the relevant biology sufficiently well to be able to modify or prevent such compensation, thereby enabling successful maintenance of therapeutic weight loss.