Role of leptin in the neuroendocrine response to fasting

脂肪细胞分泌的激素瘦素将储存在脂肪组织中的能量传递给中枢 神经系统。我们已经证明，在这项拨款的背景下，瘦素管理使 短期能量缺乏引起的相对瘦素缺乏导致生殖和生殖功能正常化 其他神经内分泌缺陷。我们还表明，在正常生理状态下改变瘦素水平 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，瘦素服务于 作为能量储备充足和下丘脑-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，这些异常现象 在下丘脑闭经(HA)妇女的生殖轴和其他神经内分泌轴中， 与低瘦素水平相关的状况，也可能与由 负能量平衡。在最近完成的一项使用历史对照的开放标签小规模试点研究中，我们 发现瘦素替代纠正HA妇女的相对瘦素缺乏导致卵泡 生长和排卵并显著改善激素水平，为瘦素提供了初步证据 可能与闭经的病因有关，瘦素替代疗法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。这项提案的目标是确认和 通过进行一项随机、双盲、安慰剂对照的试验来扩展这些初步发现 瘦素治疗HA和瘦素缺乏的妇女，将消除潜在的偏见和 并将验证瘦素作为一种新的HA治疗方法的安全性和有效性。由于医管局占了 超过30%的育龄妇女闭经，并可能对生育产生显著的有害影响， 骨骼健康和整体福祉，这项研究将有相当大的临床影响，如果瘦素成为 HA的新的、更具生理学和治疗性的选择。这一点特别相关，因为目前 HA的治疗方案有副作用，不被一些患者很好地接受，而且不是最优的 对骨质疏松症等并发症的有效性。这项研究的结果不仅有助于阐明 HA的病理生理学，也将为神经内分泌中的瘦素生理学提供重要的新信息 调节、骨代谢和免疫功能，使用HA作为慢性瘦素缺乏症的模型。 因此，本研究的发现对于阐明瘦素生理学也可能在病理生理学中有应用价值。 (可能还有治疗)其他瘦素相关疾病，包括肥胖，这是一个主要的公共卫生问题。

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.