Role of leptin in the neuroendocrine response to fasting

瘦素在禁食神经内分泌反应中的作用

• 批准号: 8037912
• 负责人: CHRISTOS S MANTZOROS
• 金额: $ 10.21万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-05 至 2011-04-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037912
• 关键词: Accounting; Acute; Adipocytes; Adipose tissue; Adverse effects; Age; Agonist; Amenorrhea; Anorexia Nervosa; Apoptosis; Attention; Behavior Therapy; Body Weight; Body Weight decreased; Bone Density; Bone Mineral Contents; Bone Resorption; Brain; Cell Proliferation; Chronic; Clinical; Clinical Research; Data; Defect; Development; Diet; Disease; Double-Blind Method; Eating; Eating Disorders; Effectiveness; Energy Metabolism; Estrogens; Etiology; Explosion; Fasting; Fatty acid glycerol esters; Fertility; Food; Food deprivation (experimental); Foundations; Functional disorder; Future; Gastrointestinal tract structure; Goals; Grant; Growth; Growth Factor; Homeostasis; Hormones; Human; Hypothalamic structure; Immune; Immune response; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Laboratories; Leptin; Leptin deficiency; Letters; Link; Long-Term Effects; Lymphocyte; Malnutrition; Mediating; Melanocortin 4 Receptor; Menstrual cycle; Modeling; Molecular; Neuraxis; Neurosecretory Systems; Obesity; Organ; Osteogenesis; Osteoporosis; Outcome; Ovulation; Paper; Pathogenesis; Pathway interactions; Patients; Peptide YY; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Physiology; Pilot Projects; Pituitary Gland; Placebos; Play; Production; Public Health; Publishing; Randomized; Recombinants; Regulation; Relative (related person); Research Design; Research Personnel; Rodent; Role; Safety; Signal Transduction; Somatotropin; Starvation; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Thyroid Gland; Well in self; Woman; adiponectin; base; bone; bone health; bone metabolism; clinical application; cytokine; density; deprivation; diet and exercise; double-blind placebo controlled trial; energy balance; falls; feeding; food restriction; ghrelin; gonad function; human subject; immune function; improved; in vivo; insight; leptin receptor; open label; programs; randomized placebo controlled trial; recombinant methionyl human leptin; reproductive; reproductive hormone; research study; resistin; response; treatment duration

The adipoeyte-secreted hormone leptin signals the amount of energy stored in adipose tissue to the central nervous system. We have shown, in the context of this grant, that leptin administration to normalize the relative leptin deficiency induced by short term energy deficiency results in normalization of reproductive and other neuroendocrine defects. We have also shown that altering leptin levels within the normal physiological range, or into supraphysiological levels, has no effect on the same outcomes. Thus, in humans, leptin serves as a critical link between the sufficiency of energy stores and the integrity of the hypothalamic-pituitary- peripheral axes in states of leptin deficiency only. We have subsequently hypothesized that the abnormalities in the reproductive and other neuroendocrine axes in women with hypothalamic amenorrhea (HA), a condition associated with low leptin levels, may also be related to the chronic hypoleptinemia induced by negative energy balance. In a recently completed, open-label, small pilot study using historical controls, we found that leptin replacement to correct the relative leptin deficiency in women with HA resulted in follicular growth and ovulation and significantly improved hormone levels, providing preliminary evidence that leptin may contribute to the etiology of the amenorrhea and that leptin replacement may be a potential treatment for disease states associated with relative leptin deficiency. The goal of this proposal is to confirm and extend these preliminary findings by performing a randomized, double-blinded, placebo-controlled trial of leptin treatment in women with HA and leptin deficiency which would eliminate potential bias and confounding and would verify safety and efficacy of leptin as a new treatment for HA. Since HA accounts for over 30% of amenorrhea in reproductive-aged women and can have significant deleterious effects on fertility, bone health, and overall well-being, this study would have considerable clinical impact if leptin becomes a new, more physiologic, therapeutic option for HA. This is particularly relevant since currently available treatment options for HA have side effects, are not well accepted by some patients, and have suboptimal effectiveness for complications such as osteoporosis. Results of this study will not only help elucidate the pathophysiology of HA but will also provide important new information on leptin physiology in neuroendocrine regulation, bone metabolism and immune function at large, using HA as a model of chronic leptin deficiency. Thus, findings of this study to elucidate leptin physiology may also have applications in the pathophysiology (and possibly therapeutics) of other leptin related diseases, including obesity, a major public health problem.

脂肪细胞分泌的激素瘦素向中枢发出脂肪组织中储存的能量信号。 神经系统。我们已经表明，在这笔资助的背景下，瘦素管理可以使 短期能量缺乏引起的相对瘦素缺乏导致生殖和功能正常化 其他神经内分泌缺陷。我们还表明，改变正常生理范围内的瘦素水平 范围或超生理水平，对相同的结果没有影响。因此，在人类中，瘦素起着 作为能量储存充足性和下丘脑-垂体完整性之间的关键环节 仅在瘦素缺乏状态下的外周轴。我们随后假设异常 在患有下丘脑闭经 (HA) 的女性的生殖轴和其他神经内分泌轴中， 与低瘦素水平相关的病症也可能与慢性低瘦素血症有关 能量负平衡。在最近完成的一项使用历史对照的开放标签小型试点研究中，我们 发现用瘦素替代来纠正患有 HA 的女性的相对瘦素缺乏会导致卵泡 生长和排卵，并显着提高激素水平，提供了瘦素的初步证据 可能导致闭经的病因，瘦素替代可能是一种潜在的治疗方法 用于与相对瘦素缺乏相关的疾病状态。该提案的目标是确认并 通过进行一项随机、双盲、安慰剂对照试验来扩展这些初步发现 对HA和瘦素缺乏的女性进行瘦素治疗，这将消除潜在的偏见和 混淆并将验证瘦素作为 HA 新疗法的安全性和有效性。由于房委会占 超过 30% 的育龄妇女出现闭经，并对生育能力产生严重的有害影响， 骨骼健康和整体健康，如果瘦素成为一种重要的临床研究，那么这项研究将产生相当大的临床影响 HA 的新的、更生理性的治疗选择。这一点特别重要，因为目前可用 HA 的治疗方案有副作用，不能被一些患者很好地接受，并且效果不佳 对骨质疏松症等并发症有效。这项研究的结果不仅有助于阐明 HA 的病理生理学，但也将提供有关神经内分泌瘦素生理学的重要新信息 使用 HA 作为慢性瘦素缺乏的模型。 因此，这项阐明瘦素生理学的研究结果也可能在病理生理学中具有应用 其他瘦素相关疾病（以及可能的治疗方法），包括肥胖这一主要的公共卫生问题。