Nutrient Sensing in Adipocytes and the Control of Oogenesis in Drosophila

描述(申请人提供)：饮食和肥胖与生育有关，但其机制在很大程度上仍不清楚。我们以前的研究表明，果蝇生殖系干细胞(GSCs)及其后代在富含酵母的饲料中分裂和生长速度快于低酵母饲料，胰岛素和雷帕霉素靶(TOR)营养传感通路在卵巢内作用于这一反应。然而，这些研究没有解决脂肪细胞感知营养影响卵巢的机制。哺乳动物的脂肪细胞信号控制着我们的大部分生理功能，包括卵巢功能。果蝇的脂肪体由脂肪细胞和肝细胞样细胞组成，也有内分泌作用。在幼虫中，依赖营养的分泌脂肪体因素影响生物体的生长；成体脂肪体如何调节卵子发生的研究较少。我们的数据显示，脂肪细胞特异性的氨基酸转运中断、TOR或胰岛素信号转导会导致不同的卵巢表型。脂肪细胞氨基酸转运减少会降低GSC数量并损害排卵。低脂肪细胞TOR信号导致排卵缺陷，但GSCs不受影响，这表明脂肪细胞氨基酸感应独立于TOR控制早期生殖细胞。与TOR的作用相反，低脂肪细胞胰岛素信号传递减少了帽子细胞(主要的生态位成分)和GSCs的数量，并损害了卵黄的形成。我们认为，不同的营养依赖机制在脂肪细胞内运作，以调节特定的分泌因子，控制卵子发生的不同阶段，从而完善卵巢对饮食的反应。为了验证这一假设，我们将(1)确定脂肪细胞胰岛素信号如何控制壁龛大小、GSC数量和卵黄发生；(2)确定脂肪细胞内氨基酸水平控制GSC数量和排卵的机制。相关性：肥胖在西方世界很普遍，会导致脂肪细胞功能异常，进而导致不孕不育。我们建议利用果蝇的强大研究工具来研究脂肪细胞在控制卵巢功能方面的正常作用。由于果蝇和人类之间分子和生物过程的高度进化保守，这项工作可能会为如何治疗肥胖相关不孕症或设计新的避孕药提供有价值的见解。

DESCRIPTION (provided by applicant): Diet and adiposity are linked to fertility, yet the mechanisms remain largely unknown. Our previous studies showed that Drosophila germline stem cells (GSCs) and their progeny divide and grow faster on yeast-rich than -poor diets, and the insulin and Target of Rapamycin (TOR) nutrient-sensing pathways act within the ovary for this response. These studies, however, did not address the mechanisms whereby nutrient sensing by adipocytes impacts the ovary. Mammalian adipocyte signals control much of our physiology, including ovarian function. The Drosophila fat body, composed of adipocytes and hepatocyte-like cells, also has an endocrine role. In larvae, nutrient-dependent secreted fat body factors affect organismal growth; how the adult fat body modulates oogenesis is less well studied. Our data show that adipocyte-specific disruption of amino acid transport, TOR or insulin signaling cause distinct ovarian phenotypes. Reduced adipocyte amino acid transport lowers GSC numbers and impairs ovulation. Low adipocyte TOR signaling causes an ovulation defect, but GSCs are unaffected, suggesting that adipocyte amino acid sensing controls early germ cells independently of TOR. In contrast to effects of TOR, low adipocyte insulin signaling reduces the numbers of cap cells (major niche components) and GSCs, and impairs vitellogenesis. We propose that distinct nutrient-dependent mechanisms operate within adipocytes to modulate specific secreted factors that control different stages of oogenesis, thereby refining the ovarian response to diet. To test this hypothesis, we will (1) determine how adipocyte insulin signaling controls niche size, GSC number, and vitellogenesis; and (2) identify the mechanisms whereby amino acid levels within adipocytes control GSC numbers and ovulation. Relevance: Obesity is prevalent in the western world, and results in the abnormal function of fat cells, which in turn can lead to infertility. We propose to take advantage of powerful research tools in fruit flies to investigate the normal role of fat cells in controlling ovarian function. Because of the high degree of evolutionary conservation of molecules and biological processes between fruit flies and humans, this work will likely provide valuable insights into how to treat obesity-related infertility or design new contraceptives.