Regulation of Leptin Synthesis and Secretion in Pregnant Mammals

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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.