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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）：肥胖已达到流行病的程度，影响了 30% 的美国人，预计到 2030 年患病率将达到 50%。肥胖患病率的增加与糖尿病、心血管疾病和癌症等不良健康结果有关。尽管成功的减肥如果持续的话可以降低负面健康结果的风险，但大多数减肥者在成功的饮食和药物治疗干预后的一段时间内恢复到基线体重。导致体重回到基线的机制仍然未知。瘦素是脂肪细胞分泌的一种蛋白质，可降低食欲并增加能量消耗。瘦素水平与肥胖程度成比例增加，循环瘦素水平随着体重减轻而降低。我们的研究小组已经证明，瘦素水平的降低会介导动物和人类对食物匮乏的神经内分泌反应。因此，与减肥相关的瘦素水平降低可能通过降低甲状腺激素水平、减少交感神经系统活动和降低代谢率来保护基线体重。尽管我们已经证明瘦素调节瘦受试者的神经内分泌功能，但上述假设从未在涉及对瘦素明显“耐受”或“抵抗”的肥胖受试者的随机对照试验中进行过研究。此外，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和瘦素信号第二信使表达的变化有关，但这些蛋白质随体重减轻而发生的任何变化从未在人类中进行过研究。我们建议通过对体重减轻的肥胖受试者进行瘦素给药的安慰剂对照、随机研究来研究瘦素在保护基线体重中的作用。通过仔细研究体重、身体成分、神经内分泌功能和代谢率，我们计划研究恢复基线体重的机制以及瘦素给药在预防这种情况方面的作用。我们还计划研究瘦素信号传导和瘦素受体表达的变化。瘦素的这种新颖且与临床相关的作用是一个迫切需要进一步研究的领域。了解减肥防御的生物学原理将有助于规划适当的长期体重维持疗法，并确保肥胖患者从减肥努力中获得长期利益。公共卫生相关性：肥胖已达到流行病的程度，影响了 30% 的美国人，预计到 2030 年患病率将达到 50%。有几种有效的治疗方法，包括生活方式干预，但大多数设法减掉临床显着体重的人通常会在数月和数年的时间内恢复体重。了解其机制并开发有效的疗法来对抗这种现象对于公共卫生具有巨大的重要性。