Leptin in Human Energy and Neuroendocrine Homeostasis

描述(由申请人提供)：即使是适量的体重减轻也会对肥胖的共病产生有益的影响。然而，体重减轻的长期维持是罕见的。我们的中心假设是，调节体内脂肪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之上。低于这一阈值的能量储存减少会引发食物摄入量和能量消耗的补偿性反应，从而恢复身体脂肪。触发这些中枢神经系统介导的变化的主要信号是脂肪细胞衍生的激素瘦素。我们已经证明，在从不肥胖和肥胖的人类中，体重保持10%或更多的减轻会导致能量消耗的减少，这主要是因为骨骼肌工作效率的提高和饥饿的增加，这两个因素协同作用，促进了身体能量储存的恢复。我们还表明，这些变化中的许多是通过给予足够剂量的外源性瘦素来正常化的，以使循环中的瘦素浓度恢复到减肥前的水平。建议的研究集中在：特定目标#1，减肥状态下的体内神经/行为生物学；以及特定目标#2，相同减肥受试者骨骼肌工作效率提高的分子生理学。在正常体重下，在减重10%之后，在减重和激素替代(使用瘦素或T3)的情况下，肥胖者和非肥胖者(居住在临床研究中心)将通过体内和体外方法进行身体成分、分区能量消耗、进食行为、自主神经系统活动、与能量摄入相关的局部神经元活动的fMRI定量研究、脑脊液神经肽/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。与公共健康相关：肥胖现在可能构成了美国最大的(且日益严重的)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代价高昂的重大疾病的影响。体重调节生物学的一个主要方面是身体坚韧地保护自己的脂肪含量，通过降低能量消耗和增加饥饿感来补偿脂肪损失，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，从而能够成功地维持治疗性减肥。

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.