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: 7991587
• 负责人: CHRISTOS S MANTZOROS
• 金额: $ 10万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-03 至 2010-12-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991587
• 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; Principal Investigator; Production; Public Health; Publishing; Randomized; Recombinants; Regulation; Relative (related person); Research Design; 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; 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; Principal Investigator; Production; Public Health; Publishing; Randomized; Recombinants; Regulation; Relative (related person); Research Design; 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.

脂肪青年分泌的激素瘦素信号向中央脂肪组织中存储的能量量 神经系统。我们已经在这笔赠款的背景下表明了瘦素给药以使其正常化 短期能量缺乏引起的相对瘦素缺乏导致生殖和 其他神经内分泌缺陷。我们还表明，在正常生理中改变瘦素水平 范围或进入超生理水平，对相同的结果没有影响。因此，在人类中，瘦素服务 作为能量存储充足性与下丘脑 - 垂体的完整性之间的关键联系 仅瘦素缺乏状态的外围轴。随后我们假设异常 在下丘脑闭经（HA）的女性的生殖和其他神经内分泌轴中 与低瘦素水平相关的疾病也可能与由 负能量平衡。在最近完成的，开放标签的小型试点研究中，我们 发现瘦素替代以纠正HA的女性相对瘦素缺乏症导致卵泡 生长和排卵，并显着改善激素水平，提供了瘦素的初步证据 可能有助于闭经的病因，而瘦素替代可能是一种潜在的治疗方法 对于与相对瘦素缺乏相关的疾病状态。该建议的目的是确认和 通过执行一项随机，双盲的安慰剂对照试验来扩展这些初步发现 HA和瘦素缺乏症女性的瘦素治疗将消除潜在的偏见和 混淆并将验证瘦素作为HA的新疗法的安全性和功效。由于HA帐户 超过30％的生殖妇女闭经，对生育能力有重大有害影响， 骨骼健康和整体幸福感，如果瘦素成为一种，这项研究将对 HA的新的，更生理的，治疗的选择。这特别重要，因为目前可用 HA的治疗选择具有副作用，某些患者不太接受，并且有优势 造成骨质疏松症等并发症的有效性。这项研究的结果不仅将有助于阐明 HA的病理生理学，但还将提供有关神经内分泌中瘦素生理学的重要新信息 使用HA作为慢性瘦素缺乏症的模型，调节，骨代谢和免疫功能总体上。 因此，这项研究阐明瘦素生理的发现也可能在病理生理学中应用 （以及可能的治疗剂）其他相关疾病，包括肥胖症，这是一个主要的公共卫生问题。