Lydia Grmai1 1Dept. of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
Reproduction is an energy-intensive process that employs multiple axes of inter-organ communication. However, the precise signaling mechanisms that relay nutrient status to modulate reproductive output are poorly understood. Here, we use Drosophila melanogaster as a model to establish the Integrated Stress Response (ISR) transcription factor Atf4 as a fat tissue metabolic sensor that instructs oogenesis. A critical role for adipocytes lies in yolk lipoprotein synthesis for trafficking to mature oocytes; we demonstrated that Atf4 regulates lipase activity to promote yolk synthesis in the fat. Depletion of Atf4 in the fat also blunts oogenesis recovery after amino acid deprivation and re-feeding, suggestive of a nutrient-sensing role for Atf4. Finally, we discovered that Atf4 promotes secretion of a fat-derived neuropeptide, CNMamide, which acts on neural circuits that promote ovulation, or egg-laying behavior. Thus, we posit that ISR signaling in fat tissue acts as a “metabolic sensor” that instructs female reproduction: directly, by impacting yolk lipoprotein synthesis and follicle maturation, and systemically, by regulating the neuronal control of ovulation. Current and future work in the Grmai Lab will tackle several questions surrounding the role of Atf4 and the ISR in reproductive regulation, including: How does Atf4 arbitrate systemic functions during homeostasis and stress? How does the ISR cooperate with steroid hormone signal transduction in reproductive regulation? To what extent does age-induced ISR changes drive systemic aging phenotypes, including reproductive senescence? This work will shed important light on how physiological stress informs reproductive output and will underscore crucial molecular players that, when dysregulated, contribute to metabolic disease and infertility in humans.
