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

描述（由申请人提供）：肥胖已经达到流行病的程度，影响了30%的美国人，预计到2030年患病率将达到50%。肥胖的日益流行与不良健康结果有关，包括糖尿病、心血管疾病和癌症。尽管减肥成功，如果持续下去，可以改善负面健康结果的风险，但大多数减重者在成功的饮食和药物治疗干预后一段时间内恢复到基线体重。这种恢复到基线体重的机制尚不清楚。瘦素是一种由脂肪细胞分泌的蛋白质，其作用是减少食欲和增加能量消耗。瘦素水平与肥胖程度成正比，循环瘦素水平随着体重减轻而下降。我们的研究小组已经证明，瘦素水平的下降介导了动物和人类对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。虽然我们已经证明瘦素调节瘦受试者的神经内分泌功能，但上述假设从未在一项随机对照试验中进行过研究，该试验涉及对瘦素明显“耐受”或“抵抗”的肥胖受试者。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，但这些蛋白在体重减轻时发生的任何变化从未在人体中进行过研究。我们建议通过对体重减轻的肥胖受试者使用瘦素进行安慰剂对照、随机研究，来研究瘦素在保护基线体重方面的作用。通过对体重、身体组成、神经内分泌功能和代谢率的仔细研究，我们计划研究恢复基线体重的机制以及瘦素在预防这种情况的作用。我们还计划研究瘦素信号和瘦素受体表达的变化。瘦素的这种新颖的临床相关作用是一个迫切需要进一步研究的领域。了解抵抗减肥的生物学将有助于制定适当的长期体重维持疗法，并确保肥胖患者从他们的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，是可用的，但是大多数成功减轻临床显著体重的人，通常会在几个月或几年的时间里重新恢复体重。了解这种现象的机制和开发有效的治疗方法对公共卫生具有重大意义。

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.