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.

Public Health 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 controllin 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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM069875-10
Application #
8758798
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Gaillard, Shawn R
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ables, Elizabeth T; Drummond-Barbosa, Daniela (2013) Cyclin E controls Drosophila female germline stem cell maintenance independently of its role in proliferation by modulating responsiveness to niche signals. Development 140:530-40
Zou, Sige; Chang, Joy; LaFever, Leesa et al. (2011) Identification of dAven, a Drosophila melanogaster ortholog of the cell cycle regulator Aven. Cell Cycle 10:989-98
LaFever, Leesa; Feoktistov, Alexander; Hsu, Hwei-Jan et al. (2010) Specific roles of Target of rapamycin in the control of stem cells and their progeny in the Drosophila ovary. Development 137:2117-26
Ables, Elizabeth T; Drummond-Barbosa, Daniela (2010) The steroid hormone ecdysone functions with intrinsic chromatin remodeling factors to control female germline stem cells in Drosophila. Cell Stem Cell 7:581-92
Hsu, Hwei-Jan; Drummond-Barbosa, Daniela (2009) Insulin levels control female germline stem cell maintenance via the niche in Drosophila. Proc Natl Acad Sci U S A 106:1117-21
Von Stetina, Jessica R; Tranguch, Susanne; Dey, Sudhansu K et al. (2008) alpha-Endosulfine is a conserved protein required for oocyte meiotic maturation in Drosophila. Development 135:3697-706
Drummond-Barbosa, Daniela (2008) Stem cells, their niches and the systemic environment: an aging network. Genetics 180:1787-97
Hsu, Hwei-Jan; LaFever, Leesa; Drummond-Barbosa, Daniela (2008) Diet controls normal and tumorous germline stem cells via insulin-dependent and -independent mechanisms in Drosophila. Dev Biol 313:700-12
LaFever, Leesa; Drummond-Barbosa, Daniela (2005) Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science 309:1071-3