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，但其机制仍然很大程度上未知。我们之前的研究表明，果蝇生殖干细胞 (GSC) 及其后代在富含酵母的饮食中分裂和生长的速度比在缺乏酵母的饮食中更快，并且胰岛素和雷帕霉素靶点 (TOR) 营养感应途径在卵巢内发挥作用以实现这种反应。然而，这些研究并没有解决脂肪细胞的营养感知影响卵巢的机制。哺乳动物脂肪细胞信号控制着我们的大部分生理机能，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子影响生物体的生长；成人脂肪体如何调节卵子发生的研究还较少。我们的数据表明，脂肪细胞特异性的氨基酸转运、TOR 或胰岛素信号传导中断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 信号传导导致排卵缺陷，但 GSC 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导会减少帽细胞（主要生态位成分）和 GSC 的数量，并损害卵黄发生。我们提出，脂肪细胞内存在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，从而改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传导如何控制微生境大小、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：肥胖在西方国家很普遍，导致脂肪细胞功能异常，进而导致不孕。我们建议利用果蝇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。由于果蝇和人类之间分子和生物过程的高度进化保守性，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具提供有价值的见解。