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

描述（由申请人提供）：这是一项试点和可行性研究，旨在研究使用瘦素对接受减肥手术但仍然肥胖的体重减轻的个体进行新的干预。瘦素是一种由脂肪组织分泌的肽激素，是食物摄入和能量消耗的调节剂。在少数报告的遗传性瘦素缺乏症的肥胖患者中，瘦素的施用导致了体重的显著减轻。然而，大多数肥胖者的瘦素水平升高。这些人被认为处于“瘦素抵抗”状态，即生理浓度的瘦素在产生显著的体重减轻方面是无效的。通过限制卡路里来减轻体重会导致瘦素水平下降，随后通常会出现体重反弹，这可能是由于相对“瘦素缺乏”状态引起的变化，从而使个体恢复到原来的体重。相比之下，Roux-en-Y胃旁路手术（RYGBP）在长期减轻体重方面比单独饮食更有效。然而，即使在手术后，体重下降也会有一个平台期，尽管患者可能仍然肥胖，并且有或有肥胖相关疾病的风险。我们已经证明，与bmi匹配的对照组相比，接受RYGBP治疗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，当给予正常情况下不会导致显著体重减轻的瘦素剂量时，体重会进一步减轻。服用RYGBP后，患者的甲状腺激素水平（部分由瘦素调节）也会下降，这可能会抵消个人进一步减肥的努力。我们还发现RYGBP与肠道激素分泌的变化有关，如血浆胰高血糖素样肽-1 （GLP-1）水平的升高。GLP-1与瘦素协同作用，使动物产生更大的饱腹感和减少食物摄入量。因此，RYGBP患者可能特别适合瘦素治疗。本研究的主要目的是验证这样一种假设，即在RYGBP治疗后，体重减轻但仍然肥胖的个体服用瘦素，与安慰剂治疗相比，体重会显著减轻。这项研究也为进一步确定瘦素对食欲感觉和参与能量稳态的神经内分泌轴的影响提供了一个独特的机会。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，以检查在RYGBP患者和通过其他方式减肥并有体重恢复高风险的个体中单独使用瘦素或与其他厌食药物联合使用瘦素。公共卫生相关性：肥胖及其相关发病率的日益普遍，使得开发有效的治疗方法来实现和保持体重减轻势在必行。不幸的是，目前的选择往往无法产生长期的减肥效果。这一建议将确定瘦素激素是否能在接受过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的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.