Regulation of Leptin Synthesis and Secretion in Pregnant Mammals

总体而言，啮齿动物和蝙蝠约占所有已知哺乳动物物种的75%。在翼手目中，温带蝙蝠，如小棕色蝙蝠(Myotis Lucifugus)，在美国和其他地方扮演着关键的生态和经济角色。例如，这些物种在控制昆虫种群方面很重要，否则在没有食虫蝙蝠的情况下，昆虫种群就会蓬勃发展。因此，了解这些物种的基本生殖过程的调节是至关重要的，但令人惊讶的是，蝙蝠生殖控制的许多基本方面仍然不清楚。使用比较方法将提供有关这些监管过程的普遍性的信息。最近，所谓的肥胖激素，瘦素，被认为在哺乳动物的繁殖中起到了作用。这一假说最初源于观察到怀孕动物血液中的瘦素水平显著增加。瘦素的既定功能是当体重增加时抑制食欲和刺激代谢率。随着体内脂肪量的增加，脂肪细胞会将瘦素分泌到血液中，这向大脑发出信号，表明有足够的脂肪储备。瘦素是否在生殖过程中发挥调节作用仍不确定。同样不确定的是怀孕期间血浆瘦素水平升高的机制(S)。最近的证据表明，胎盘和脂肪组织在妊娠期间都是分泌瘦素的重要组织，而且瘦素不仅可能由胎盘分泌，还可能对其起作用(例如，促进胎盘的生长和发育)。在这个项目中，将确定在哺乳动物生活史上这段高能量要求的时期，影响两种组织来源瘦素分泌的调节因素。进一步提出的实验将允许确定瘦素是否由啮齿动物和蝙蝠的胎盘主动合成。最后，实验将对这一假设进行测试，即大脑瘦素受体表达的变化在一定程度上解释了怀孕期间观察到的瘦素不敏感(即，怀孕的女性在这种抑制食欲的荷尔蒙水平上升的情况下继续吃得高于正常水平的能力)。这样的实验可能有助于解释为什么有些人显然对瘦素抑制食欲的作用不敏感。这些研究将扩大我们对翼手目生殖过程的了解，特别是将胎盘作为哺乳动物的内分泌器官，也将适用于其他哺乳动物目，因为例如蝙蝠和人类在怀孕期间对瘦素分泌的控制似乎类似。阐明蝙蝠瘦素及其受体的序列将为检测大脑和胎盘中瘦素受体的存在提供有用的探针，并有助于未来对该蛋白的系统发育和结构/功能的分析。该项目还将通过包括许多将参与该项目不同阶段的本科生以及几名研究生或博士后研究员来为科学教育做出贡献。这些学生将在野外生物学和实验室生物学方面获得宝贵的双重经验，同时从事一个对整个社会具有广泛影响和好处的非常专题的项目。国际科学协会和联合国际通过各级研究和教学，从K-12到大学，以及高中科学教师的继续教育，促进科学发展，有着悠久而成功的历史。预计这一趋势将在这一新项目中继续下去。

Collectively, rodents and bats comprise roughly 75% of all known mammalian species. Within the Chiroptera, temperate bats such as the little brown bat (Myotis lucifugus) play critical ecological and economic roles in the United States and elsewhere. For example, these species are important in controlling insect populations, which would otherwise flourish in the absence of insectivorous bats. Understanding the regulation of basic reproductive processes in these species is therefore of vital concern, but surprisingly many fundamental aspects of reproductive control are still unclear in bats. The use of a comparative approach will provide information on the ubiquity in nature of these regulatory processes. Recently, the so-called obesity hormone, leptin, has been suggested to serve a role in mammalian reproduction. This hypothesis originally arose from the observation that levels of leptin in blood of pregnant animals increase considerably. Leptin's established functions are to suppress appetite and stimulate metabolic rate when body weight increases. As fat mass in the body increases, adipose cells secrete leptin into the blood, which signals the brain that sufficient fat reserves are available. Whether leptin exerts regulatory effects during reproduction is still uncertain. Also uncertain is the mechanism(s) by which plasma leptin levels are elevated during pregnancy. Recent evidence suggests that both the placenta and adipose tissue are important in secreting leptin during pregnancy, and that leptin may not only be secreted by the placenta, but may act on it as well (e.g., to promote its growth and development). In this project the regulatory factors that influence leptin secretion from both tissue sources during this energetically-demanding period of a mammal's life history will be identified. Further proposed experiments will permit determination of whether leptin is actively synthesized from placentas of rodents and bats. Finally, experiments will provide tests of the hypothesis that changes in expression of brain leptin receptors account in part for observed leptin-insensitivity during pregnancy (i.e., the ability of pregnant females to continue eating above a normal amount despite elevated levels of this appetite-suppressing hormone). Such experiments may help explain why some people are apparently insensitive to the appetite-suppressing effects of leptin. These studies will extend our knowledge of reproductive processes in Chiroptera, specifically, of the placenta as a mammalian endocrine organ, and will also be applicable to other mammalian orders, since the control of leptin secretion during pregnancy appears similar in bats and humans, for example. Elucidation of the sequence of leptin and its receptor in bats will provide useful probes for detecting the presence of receptor in brain and placenta, and aid in future phylogenetic and structure/function analyses of the protein. This project will also contribute to science education by including numerous undergraduate students who will participate in various phases of the project, plus several graduate students or post-doctoral fellows. These students will gain valuable dual experience in field and laboratory biology, while engaged in an extremely topical project with wide-ranging ramifications and benefits to society at large. The PI and the co-PI have a long and successful history of promoting science through research and teaching at all levels, from K-12 through college, and continuing education of high school science teachers. It is anticipated that this trend will continue with this new project.