noNutritional status regulates energetically costly functions such as reproduction.1 Adipose tissue acts as both an energy reservoir and a metabolic sensor that acts through a series of transcription factors and effector proteins termed the integrated stress response (ISR).2 However, the mechanisms that fat uses to communicate nutritional status to tissues such as the ovaries are not well understood.
In published studies, Cell ReportA research team from the University of Pittsburgh Drosophila melanogaster Regulating reproduction based on metabolic stress.3 The findings could help answer questions about infertility resulting from nutritional imbalances.
“When you’re trying to understand how tissues communicate with each other, one of the general trends is that there are probably factors that are responsible for this communication,” says Alisa Armstrong, a cell and reproductive biologist at the University of South Carolina, who was not involved in the study. “Until now, it’s been very elusive to know what those factors are.”
“We think of stress responses as a way for organisms and cells to cope with external factors, but evolutionarily speaking, we now know that these stress-response mechanisms are only important for homeostatic function,” says Deepika Vasudevan, a cell biologist at the University of Pittsburgh and an author of the study. She previously Hidden skullthe fly homologue of the ISR gene Activating transcription factor 4 (ATF4 is) reduced oocyte maturation, increased cell death, and caused developmental arrest in humans.Four
In the present study, Vasudevan and her team investigated the mechanism behind this fertility defect: they created a knockdown fly model in which they reduced expression of Atf4 (Atf4 KD). ATF4 is This is especially evident in the fat tissue of animals. The mutation causes developing oocytes, called follicles, to die early during maturation or oogenesis, as has been observed before. However, the researchers noted that this most frequently occurs at the stage when follicles get a large amount of lipoproteins, called yolk proteins, from fat cells. They observed that depleting Atf4 in the fat tissue of flies reduced the amount of yolk protein produced by fat cells, limiting the availability of this nutrient to send to the follicles.
Because Atf4 is involved in nutrient-sensing signaling, the team investigated whether this also led to impaired oocyte growth. They fed wild-type and Atf4 KD flies a nutrient-deficient diet and observed increased follicle death in both groups. However, these effects were reversed when normal flies were returned to a standard diet, whereas Atf4 KD flies did not recover.
“At that point, we already knew that if you remove the stressors in the fat tissue, egg formation becomes less efficient,” explains Lydia Gurmai, a cell biologist and postdoctoral researcher in Vasudevan’s lab. Gurmai suspected she’d made a mistake when she saw that the mutant flies had more eggs in their ovaries. Other experiments later yielded the same results. “We eventually came to the conclusion that, ‘Well, maybe they can make eggs, but they’re no longer laying eggs,'” she says.
“[Grmai] “In this study, we saw a defect in the ability to lay eggs, which is primarily a neuronal defect,” Vasudevan said. This led the team to investigate neuropeptides under the control of Atf4. They looked at publicly available chromatin immunoprecipitation sequence data and found four candidate genes.
After individually deleting each gene in the fat tissue, the researchers CNThe C-terminal motif of Atf4, which encodes the neuropeptide of the same name, had the greatest effect on ovulation. To confirm that the reduction in this neuropeptide caused egg retention by reducing Atf4 activity, the researchers CN expression in Atf4 KD animals and a reduction in mature oocytes retained in the fly ovaries was observed.
“It’s exciting to know that we’ve identified a specific neuropeptide that is actually secreted by adipose tissue and communicates with a receptor in the brain,” Armstrong said. She noted that they’re also interested in learning what other steps in oocyte maturation and ovulation this signaling pathway affects.
Vasudevan and Gurumai are interested in further exploring the molecular mechanisms and targets of this system, but believe their work has revealed a potential regulatory interface. “This signaling event in adipose tissue may have this kind of regulatory role, so that it can sense the environment and relay those signals to different tissues,” Gurumai says. The researchers believe their work has broad implications that can help understand reproductive biology, lipid biology and homeostatic control.
References
- Lin KY, Hsu HJ. Regulation of adult female germline stem cells by nutrient-responsive signaling. Curr Opin Insect Sci. 2020;37:16-22
- Han J, Kaufman RJ. Role of ER stress in lipid metabolism and lipotoxicity. Journal of Lipid Research 2016;57(8):1329-1338
- Grmai L, et al. Integrated stress response signaling functions as a metabolic sensor in adipose tissue to control oocyte maturation and ovulation. Cell Personnel 2024;43(3):113863
- Vasdudevan D, et al. Protein trap alleles reveal roles Drosophila ATF4 in photoreceptor degeneration, oogenesis, and wing development. Dismodel mecha. 2022;15(3): dmm049119