Nutrient Sensing in Adipocytes and the Control of Oogenesis in Drosophila

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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.