Role of the neuroendocrine axis and its link with obesity in the genesis of PCOS

Project Information

DROPCOS

Grant agreement ID: 101109123

DOI

10.3030/101109123

Project closed

EC signature date 14 March 2023

Start date 1 May 2023

End date 30 April 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 181 152,96

Coordinated by

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain

Periodic Reporting for period 1 - DROPCOS (Role of the neuroendocrine axis and its link with obesity in the genesis of PCOS)

Reporting period: 2023-05-01 to 2025-04-30

Summary of the context and overall objectives of the project

Polycystic Ovary Syndrome (PCOS) is the most common hormonal disorder among women of reproductive age, affecting up to 15% of women globally. Despite its high prevalence and major impacts on reproductive health, fertility, metabolism, and mental wellbeing, the causes of PCOS remain unclear, and no definitive cure currently exists. This gap in knowledge severely limits the development of targeted therapies and preventive strategies.
The DROPCOS project aimed to develop and utilize a novel genetic animal model of PCOS, using Drosophila melanogaster, to uncover the biological mechanisms underlying the syndrome. While PCOS is typically diagnosed during adolescence or adulthood, emerging evidence suggests that its roots may lie much earlier in life, potentially even during embryonic development. The project aimed to test this hypothesis by examining how neuroendocrine signaling, fat metabolism, and ovarian development are coordinated during early life stages.
Specifically, the project investigated the role of genes involved in inter-organ communication, particularly between the brain, fat body (the fly equivalent of adipose tissue), and ovaries. The central objective was to characterize how disruptions in this neuroendocrine-adipose-gonadal axis can lead to PCOS-like features, such as excess germline stem cell proliferation, cystic ovaries, and metabolic imbalances.
This project contributes to addressing a major global health issue and provides a cost-effective, high-throughput genetic platform for exploring potential therapeutic targets and early biomarkers of PCOS.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The DROPCOS project aimed to investigate the developmental and metabolic origins of PCOS using an innovative fruit fly model. By combining advanced genetics, microscopy, single-cell genomics, and metabolomics, the project successfully recreated several key features of PCOS that are observed in humans, including ovarian abnormalities, altered fat metabolism, and reduced fertility.
Throughout the course of the project, genetically modified fruit flies were engineered to mimic PCOS-like conditions. Analysis of the female larval gonads in these models revealed a clear developmental arrest, where ovarian cells remained in an immature state and accumulated excessive numbers of proliferating stem cells. Importantly, for the first time, adult females from the PCOS-like line survived to adulthood and exhibited hallmark traits of PCOS, such as increased body weight and subfertility, further validating the fly as a model for this complex condition.
In addition, high-quality single-cell transcriptomic data were generated from neuroendocrine cells and gonadal tissues of both healthy and PCOS-like larvae. This data will be instrumental in identifying disrupted gene regulatory networks associated with the syndrome, providing a valuable resource for understanding the cellular transitions affected in PCOS.
The project also explored the role of fat metabolism in the syndrome. Comprehensive lipidomic and metabolomic analyses identified specific metabolic signatures in PCOS-like larvae and adults. These findings indicate a systemic metabolic imbalance that mirrors the metabolic dysfunctions seen in women with PCOS.
Further functional experiments highlighted the role of inter-organ communication in the pathophysiology of PCOS. Early results support a model in which disrupted signaling from the fat body to the ovaries contributes to the emergence of PCOS features.
Overall, DROPCOS has made substantial progress in developing a genetically tractable model of PCOS. It has uncovered both cellular and metabolic mechanisms that may underlie this common yet poorly understood syndrome. The results lay the groundwork for future research into early diagnosis and targeted therapies, demonstrating the utility of Drosophila as a model for complex endocrine disorders.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project has produced several innovative findings that advance the current understanding of PCOS research. It has created the first genetic model of PCOS-like pathology using invertebrates, which allows for an unprecedented level of genetic control and the potential for high-throughput functional screening. This model offers a novel perspective on the origins of PCOS, suggesting that the syndrome may result from early developmental disruptions in neuroendocrine and adipose tissue signaling, rather than being solely attributed to a hormonal imbalance that develops in adulthood.
One of the key discoveries is the identification of fat-derived signals and axon-guidance molecules as crucial regulators of ovarian development and fertility. These findings shift the focus toward systemic and developmental factors contributing to the disease. Additionally, the use of single-cell transcriptomic and epigenomic technologies in the Drosophila ovary has opened new avenues to investigate how stem cell niches and cellular differentiation pathways are altered at the onset of disease, providing a detailed view of cellular dynamics within affected tissues.
The broader implications of these findings are significant. They could influence future research aimed at understanding the early-life origins of PCOS, promote drug discovery efforts targeting newly identified molecular pathways, and support the development of translational studies using vertebrate models. To facilitate the widespread dissemination and utilization of these results, both the model and its associated datasets will be made available to the scientific community. Moving forward, further research will be essential to validate these findings in mammalian systems and to identify potential biomarkers or therapeutic targets that could lead to clinically relevant interventions.

Graphical Abstract of DROPCOS project