Effects of Leptin on Body Weight and Neuroendocrine Axes after Gastric Bypass

描述（由申请人提供）： 这是一个试点和可行性研究，以检查一种新的干预措施，使用瘦素在减肥的个人谁经历了减肥手术，但仍然肥胖。瘦素是一种由脂肪组织分泌的肽类激素，是食物摄入和能量消耗的调节因子。在少数报告的遗传性瘦素缺乏的肥胖个体病例中，瘦素的施用导致了体重的显著减轻。然而，大多数肥胖的人都增加了瘦素水平。据说这些人处于“瘦素抵抗”状态，即给予生理浓度的瘦素对显着减轻体重无效。通过热量限制减肥导致瘦素水平降低，并且通常随后体重恢复，这可能是由于相对的“瘦素缺乏”状态引起的变化，其作用是使个体恢复到他或她的原始体重。相比之下，Roux-en-Y胃旁路手术（RYGBP）在长期减轻体重方面比单纯饮食更有效。然而，即使在手术后，体重减轻也有一个平台期，尽管个体可能仍然肥胖，并且患有肥胖相关的疾病或处于肥胖相关的疾病的风险中。我们发现，与BMI匹配的对照组相比，RYGBP后的女性血浆瘦素水平显著降低。这种相对低瘦素血症或瘦素不足的状态表明，RYGBP后个体可能处于瘦素敏感状态，因此，当给予通常不会导致显著体重减轻的瘦素剂量时，将经历进一步的体重减轻。在RYGBP之后，患者的甲状腺激素水平也会下降（部分由瘦素调节），这可能会抵消个体进一步减肥的尝试。我们还发现RYGBP与肠道激素分泌的变化有关，例如血浆胰高血糖素样肽-1（GLP-1）水平的增加。GLP-1与瘦素协同作用，在动物中引起更大的饱足感和减少的食物摄入。因此，RYGBP患者可能特别适合对瘦素治疗作出反应。本研究的主要目的是检验以下假设：与安慰剂治疗相比，RYGBP后体重减轻但仍肥胖的个体给予瘦素将导致体重显著降低。这项研究也提供了一个独特的机会，进一步确定瘦素对食欲的感觉和参与能量稳态的神经内分泌轴的影响。如果这项研究的结果支持我们的假设，那么将进行进一步的研究，以检查单独使用瘦素或与其他厌食剂联合使用RYGBP患者和通过其他方式减轻体重并具有体重恢复高风险的个体。公共卫生相关性：肥胖症及其相关疾病的日益普遍使得开发有效的治疗方法以实现和维持减轻的体重成为当务之急。不幸的是，目前的选择往往是无效的，在产生长期的体重减轻。这项提案将确定激素瘦素是否可以在接受减肥手术但仍然肥胖的个体中产生减肥效果，并可能为非手术方式长期减肥提供新的策略。

DESCRIPTION (provided by applicant): This is a pilot and feasibility study to examine a novel intervention using leptin in weight-reduced individuals who have undergone bariatric surgery but still remain obese. Leptin, a peptide hormone secreted from adipose tissue, is a regulator of food intake and energy expenditure. Administration of leptin resulted in profound weight reduction in the few reported cases of obese individuals with genetic leptin deficiency. However, most obese people have increased leptin levels. Such individuals are said to be in a 'leptin- resistant' state, whereby administration of physiological concentrations of leptin are ineffective at producing significant weight reduction. Weight loss by calorie restriction results in decreased leptin levels and is usually followed by weight regain likely due to changes induced by a relative 'leptin-deficient' state that act to return an individual to his or her original weight. In contrast, Roux-en-Y gastric bypass surgery (RYGBP) is more effective than diet alone in producing long-term reduction of body weight. Yet even after surgery there is a plateau in weight loss though the individual may still be obese and have or be at risk for obesity related morbidities. We have shown that plasma leptin levels are significantly lower in women after RYGBP compared with BMI-matched controls. This state of relative hypoleptinemia or leptin insufficiency suggests that post-RYGBP individuals may be in a leptin-sensitive state and, thus, would undergo further weight loss when administered doses of leptin that would not normally result in significant weight reduction. After RYGBP patients also have a decline in thyroid hormone levels (which are regulated in part by leptin) that may counteract an individual's attempt at further weight reduction. We have also shown that RYGBP is associated with changes in gut hormone secretion, such as increased levels of plasma glucagon-like peptide-1 (GLP-1). GLP-1 acts synergistically with leptin to cause greater satiation and decreased food intake in animals. Thus, RYGBP patients may be particularly suited to respond to leptin therapy. The main objective of this study is to test the hypothesis that administration of leptin to weight reduced, but still obese, individuals after RYGBP will result in a significant reduction in body weight compared with placebo treatment. This study also provides a unique opportunity to further define the effects of leptin on appetitive sensations and neuroendocrine axes involved in energy homeostasis. If results from this study support our hypothesis, then further studies will be undertaken to examine the use of leptin alone or in combination with other anorectic agents in RYGBP patients and in individuals who have undergone weight reduction by other means and are at high risk for weight regain. PUBLIC HEALTH RELEVANCE: The increasing prevalence of obesity and its related morbidities makes it imperative to develop effective treatments to achieve and maintain a reduced body weight. Unfortunately current options are often ineffective at producing long-term weight reduction. This proposal will determine if the hormone leptin can produce weight loss in individuals who have undergone weight loss surgery but are still obese and may provide a new strategy for long-term weight reduction with non-surgical modalities.