The Role of Leptin in the Maintenance of a Reduced Body Weight

瘦素在维持减轻体重方面的作用

基本信息

批准号：
8286384
负责人：
CHRISTOS S MANTZOROS
金额：
$ 35.41万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286384
关键词：
Accounting Adipocytes Adult Affect American Animals Area Basal metabolic rate Basic Science Biology Body Composition Body Weight Body Weight decreased Cachexia Cardiovascular Diseases Chromosomes, Human, Pair 7 Clinical Trials Code Controlled Clinical Trials Defect Desire for food Diabetes Mellitus Diet Dose Eating Endocrine Energy Intake Energy Metabolism Ensure Epidemic European Fasting Fatty acid glycerol esters Food deprivation (experimental)Future Genes Health Homeostasis Hormones Human Hyperinsulinism Hyperphagia Individual Insulin Insulin Resistance Intervention Investigation Klinefelter&apos s Syndrome Leptin Leptin deficiency Leukocytes Link Magic Maintenance Maintenance Therapy Malignant Neoplasms Mediating Medical Metabolic Modeling Mus Mutation Natural History Neurosecretory Systems Obese Mice Obesity Outcome Overweight Pathway interactions Patients Persons Pharmacotherapy Phase Physiological Physiology Pilot Projects Placebo Control Placebos Prevalence Proteins Puberty Public Health Randomized Randomized Controlled Trials Receptor Activation Reporting Research Design Resistance Risk Role Second Messenger Systems Signal Transduction Starvation Sympathetic Nervous System Therapy Clinical Trials Thyroid Hormones Time Tissues Uncontrolled Study Weight Weight Gain Woman bariatric surgery clinical application clinically relevant clinically significant combat design early onset effective therapy energy balance falls improved increased appetite insight interest leptin receptor lifestyle intervention meetings men novel obesity treatment placebo controlled study positional cloning prevent psychologic randomized placebo controlled trial receptor expression recombinant methionyl human leptin reproductive response second messenger weight maintenance

项目摘要

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions, affecting 30% of Americans, with a projected prevalence of 50% by 2030. The increasing prevalence of obesity has been associated with adverse health outcomes including diabetes, cardiovascular disease and cancer. Despite successful weight loss that could, if sustained, improve risk of negative health outcomes, the majority of weight reduced persons return to baseline body weight over a period of time following successful dietary and pharmacotherapy intervention. The mechanisms responsible for this return to baseline bodyweight remain unknown. Leptin is a protein secreted by adipocytes which acts to reduce appetite and increase energy expenditure. Leptin levels are increased in proportion to the degree of adiposity and circulating leptin levels decrease with weight loss. Our group has shown that decreasing leptin levels mediate the neuroendocrine response to food deprivation in both animals and humans. Thus, reduced leptin levels associated with weight loss could be responsible for defending baseline body weight by reducing thyroid hormone levels, reducing sympathetic nervous system activity and reducing metabolic rate. Although we have demonstrated that leptin regulates neuroendocrine function in lean subjects, the above hypothesis has never been studied in the setting of a randomized, controlled trial involving obese subjects who are apparently "tolerant" or "resistant" to leptin. Also, although animal studies indicate that leptin sensitivity is associated with changes in the expression of leptin receptor and second messengers of leptin signaling in leptin sensitive tissues, any changes that occur in these proteins with weight loss have never been studied in humans. We propose to study the role of leptin in defending baseline body weight by performing a placebo-controlled, randomized study of leptin administration to weight reduced obese subjects. By careful study of body weight, body composition, neuroendocrine function and metabolic rate, we plan to study the mechanisms involved in return to baseline body weight and the effect of leptin administration in preventing this. We also plan to study the changes in leptin signaling and leptin receptor expression. This novel and clinically relevant role for leptin is an area that urgently requires further study. Understanding the biology of the defense against weight loss will help to plan appropriate long-term weight maintenance therapies and ensure that obese patients derive long-term benefit from their efforts to reduce weight. PUBLIC HEALTH RELEVANCE: Obesity has reached epidemic proportions, affecting 30% of Americans, with a projected prevalence of 50% by 2030. Several effective therapies, including lifestyle interventions, are available however the majority of individuals who manage to lose a clinically significant amount of weight, generally regain that weight over a period of months and years. Understanding the mechanisms and developing effective therapies to combat this phenomenon is of huge public health importance.

描述（由申请人提供）：肥胖已经达到流行病，影响了30％的美国人，预计到2030年的患病率为50％。肥胖症患病率的增加与包括糖尿病，心血管疾病和癌症在内的不良健康结局有关。尽管成功的体重减轻，如果持续下去，可以改善健康状况不良的风险，但在成功的饮食和药物治疗干预后，大多数体重减轻会减轻体重。造成这种恢复至基线体重的机制仍然未知。瘦素是脂肪细胞分泌的蛋白质，可减少食欲并增加能量消耗。瘦素水平与肥胖程度成正比，循环瘦素水平随体重减轻而降低。我们的小组表明，瘦素水平降低介导动物和人类食物剥夺的神经内分泌反应。因此，与体重减轻相关的瘦素水平降低可能是通过降低甲状腺激素水平，降低交感神经系统活性并降低代谢率来捍卫基线体重的原因。尽管我们已经证明了瘦素调节精益受试者的神经内分泌功能，但在涉及肥胖受试者的随机，对照试验的情况下，从未对上述假设进行研究，这些试验显然对瘦素具有“耐受性”或“抗性”。同样，尽管动物研究表明，瘦素敏感性与瘦素敏感组织中瘦素受体的表达和瘦素信号的第二个使者的表达有关，但在这些蛋白质中发生的任何变化都从未在人类中研究过。我们建议通过进行安慰剂对照的，随机研究瘦素给药以减少肥胖受试者来研究瘦素在捍卫基线体重中的作用。通过仔细研究体重，身体成分，神经内分泌功能和代谢率，我们计划研究涉及基线体重的机制以及瘦素给药在预防这种情况下的影响。我们还计划研究瘦素信号传导和瘦素受体表达的变化。瘦素的这种新颖和临床相关的作用是迫切需要进一步研究的领域。了解防御体重减轻的生物学将有助于计划适当的长期体重维持疗法，并确保肥胖患者从减轻体重的努力中获得长期受益。公共卫生相关性：肥胖已经达到了流行病的比例，影响了30％的美国人，预计到2030年的患病率为50％。但是，多种有效的疗法，包括生活方式干预措施，但是大多数人都可以减轻临床上大量的体重，通常会在几个月和几年的时间内恢复这种体重。了解与这种现象作用的机制和开发有效的疗法具有巨大的公共健康重要性。