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

瘦素对胃绕道手术后体重和神经内分泌轴的影响

• 批准号: 7583938
• 负责人: Judith Korner
• 金额: $ 22.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583938
• 关键词: Adipose tissue; Affect; Animals; Appetite Depressants; Body Weight; Body Weight decreased; Caloric Restriction; Case Study; Catecholamines; Cholecystokinin; Development; Diet; Dose; Double-Blind Method; Eating; Endocrine; Energy Metabolism; Esthesia; Fatty acid glycerol esters; Feasibility Studies; Feeling; Gastric Bypass; Genetic; Homeostasis; Hormones; Hunger; Hydrocortisone; Individual; Intervention; Leptin; Leptin deficiency; Link; Metabolic; Modality; Morbidity - disease rate; Neurosecretory Systems; Obesity; Operative Surgical Procedures; Patients; Peptide YY; Physiological; Placebo Control; Placebos; Plasma; Prevalence; Relative (related person); Resistance; Risk; Salivary; Satiation; Signal Transduction; Testing; Thyroid Hormones; Urine; Weight; Woman; bariatric surgery; effective therapy; ghrelin; glucagon-like peptide 1; high risk; novel; obesity risk; peptide hormone; public health relevance; recidivism; urinary

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.

描述（由申请人提供）：这是一项试点和可行性研究，旨在检验一种使用瘦素对已接受减肥手术但仍然肥胖的减重个体进行的新型干预措施。瘦素是一种从脂肪组织分泌的肽激素，是食物摄入和能量消耗的调节剂。在少数报道的患有遗传性瘦素缺乏症的肥胖个体中，服用瘦素可显着减轻体重。然而，大多数肥胖者的瘦素水平升高。据说这样的个体处于“瘦素抗性”状态，由此施用生理浓度的瘦素对于产生显着的体重减轻是无效的。通过限制热量摄入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 胃绕道手术 (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，体重减轻仍会达到平台期，尽管个体可能仍然肥胖并且患有肥胖相关疾病或有肥胖相关疾病的风险。我们发现，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着降低。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，当服用通常不会导致体重显着减轻的瘦素剂量时，体重会进一步减轻。 RYGBP 治疗后，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尝试。我们还表明，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) 水平升高。 GLP-1 与瘦素协同作用，使动物产生更大的饱腹感并减少食物摄入。因此，RYGBP 患者可能特别适合对瘦素治疗有反应。本研究的主要目的是检验以下假设：与安慰剂治疗相比，在 RYGBP 治疗后，对体重减轻但仍然肥胖的个体施用瘦素将导致体重显着减轻。这项研究还提供了一个独特的机会来进一步确定瘦素对食欲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，以检查瘦素在 RYGBP 患者以及通过其他方式减肥且体重反弹风险较高的个体中单独使用或与其他减食欲药物联合使用。公共卫生相关性：肥胖及其相关疾病的患病率不断增加，因此必须开发有效的治疗方法来实现并维持减轻的体重。不幸的是，当前的选择通常无法有效实现长期减肥。该提案将确定激素瘦素是否可以使接受过减肥手术但仍然肥胖的个体减轻体重，并可能为非手术方式的长期减肥提供新策略。