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

描述(由申请人提供)：这是一项试验性和可行性研究，旨在研究一种使用瘦素对接受减肥手术但仍肥胖的减肥患者进行干预的新方法。瘦素是一种由脂肪组织分泌的多肽激素，是食物摄入量和能量消耗的调节器。在少数报道的患有遗传性瘦素缺乏症的肥胖者中，服用瘦素可显著减轻体重。然而，大多数肥胖者的瘦素水平都有所上升。这些人被认为处于“瘦素抵抗”状态，在这种状态下，服用生理浓度的瘦素在显著减轻体重方面无效。通过限制卡路里的摄入来减肥会导致瘦素水平降低，通常会导致体重恢复，这是由于相对的瘦素缺乏状态导致的变化，这种状态会让一个人恢复到原来的体重。相比之下，Roux-en-Y胃旁路手术(RYGBP)在产生长期体重减轻方面比单纯饮食更有效。然而，即使在手术后，体重下降也有一个平台期，尽管个人可能仍然肥胖，并有或处于肥胖相关疾病的风险中。我们已经表明，与体重指数匹配的对照组相比，服用RYGBP后女性的血浆瘦素水平显著降低。这种相对低血症症或瘦素不足的状态表明，RYGBP后的个体可能处于瘦素敏感状态，因此，当给予正常情况下不会显著减轻体重的瘦素剂量时，将进一步减轻体重。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)，这可能会抵消个人进一步减肥的尝试。我们还表明，RYGBP与胃肠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，导致动物更大的饱腹感和更少的食物摄入。因此，RYGBP患者可能特别适合瘦素治疗。这项研究的主要目的是验证这样一种假设：与安慰剂治疗相比，RYGBP治疗后体重减轻但仍肥胖的人的瘦素治疗将导致显著的体重减轻。这项研究还提供了一个独特的机会，进一步确定瘦素对食欲感觉和参与能量动态平衡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，以检查瘦素单独或与其他厌食剂联合用于RYGBP患者和通过其他方式减轻体重并具有高体重恢复风险的个人。公共卫生相关性：肥胖症及其相关疾病的流行日益增加，因此必须开发有效的治疗方法来实现和保持减轻体重。不幸的是，目前的选择往往在产生长期减肥效果方面效果不佳。这项建议将确定激素瘦素是否能在接受减肥手术但仍肥胖的个人中产生减肥效果，并可能为非手术方式的长期减肥提供一种新的策略。

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.