Nutrient Sensing in Adipocytes and the Control of Oogenesis in Drosophila

脂肪细胞的营养感应和果蝇卵子发生的控制

• 批准号: 8758798
• 负责人: Daniela Drummond-Barbosa
• 金额: $ 33.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758798
• 关键词: Address; Adipocytes; Adult; Affect; Amino Acids; Binding; Biological; Biological Process; Cell Count; Cell physiology; Cells; Contraceptive Agents; Contraceptive methods; Data; Defect; Diet; Drosophila genus; Endocrine; F Factor; Fat Body; Feedback; Female; Fertility; Fetus; Germ; Germ Cells; Growth; Hepatocyte; Human; Infertility; Insulin; Larva; Lead; Link; Lipids; Mediating; Mitosis; Modeling; Molecular; Nutrient; Obesity; Oogenesis; Ovarian; Ovary; Ovulation; Pathway interactions; Peptides; Phenotype; Phosphotransferases; Physiological Processes; Physiology; Protein Biosynthesis; Reproduction; Research; Role; Signal Transduction; Sirolimus; Staging; Stem cells; Testing; Text; Time; Transfer RNA; Translations; Vitellogenesis; Western World; Woman; Work; Yeasts; cytokine; design; detection of nutrient; insight; insulin signaling; lipophorin; public health relevance; response; stem cell division; therapeutic target; tool

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.

描述（由申请人提供）：饮食和肥胖与生育能力有关，但这些机制在很大程度上尚不清楚。我们先前的研究表明，果蝇种系干细胞（GSC）及其后代分裂并在酵母饮食上生长更快，而繁殖饮食的胰岛素和靶标在卵巢内作用于卵巢内的胰岛素和靶标。然而，这些研究并未解决脂肪细胞营养感应影响卵巢的机制。哺乳动物脂肪细胞信号控制着我们的许多生理学，包括卵巢功能。果蝇脂肪体，由脂肪细胞和肝细胞样细胞组成，也具有内分泌作用。在幼虫中，营养依赖性分泌的脂肪体因素会影响有机体生长。成年脂肪体如何调节卵子的研究较少。我们的数据表明，氨基酸转运，TOR或胰岛素信号传导的脂肪细胞特异性破坏会导致不同的卵巢表型。减少的脂肪细胞氨基酸转运降低了GSC数量并损害排卵。低脂肪细胞TOR信号传导会导致排卵缺陷，但GSC不受影响，表明脂肪细胞氨基酸传感可独立于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导减少了盖细胞（主要细分成分）和GSC的数量，并损害了植物生成。我们建议在脂肪细胞中起作用不同的营养依赖性机制，以调节控制卵子发生不同阶段的特定分泌因子，从而完善卵巢对饮食的反应。为了检验这一假设，我们将（1）确定脂肪细胞胰岛素信号如何控制利基大小，GSC数和植物生成； （2）确定脂肪细胞中氨基酸水平控制GSC数量和排卵的机制。相关性：肥胖症在西方世界很普遍，导致脂肪细胞的异常功能，进而导致不育症。我们建议利用果蝇中强大的研究工具来研究脂肪细胞在控制卵巢功能中的正常作用。由于水果蝇与人之间的分子和生物过程的进化保护很高，这项工作可能会为如何治疗与肥胖相关的不孕症或设计新的避孕药提供宝贵的见解。