PR002681 (Project)

Description:PROJECT SUMMARY Reproduction requires the integration of nutrient availability and lipid metabolism to sustain oogenesis and ensure fertility. Disruptions in this metabolic balance are strongly associated with reproductive failure, yet the mechanisms that coordinate these processes remain poorly defined. This project aimed to dissect how lipid metabolic pathways intersect with nutrient-sensing signals to govern germ cell differentiation. Specifically, we focused on the role of Acetyl-CoA Carboxylase (ACC), the rate-limiting enzyme for fatty acid synthesis, in maintaining oocyte development. We demonstrate that ACC functions as a key metabolic regulator by sustaining endosomal trafficking and modulating nutrient-responsive TOR signalling. Loss of ACC activity shifts metabolism toward fatty acid oxidation (FAO), which increases flux through the tricarboxylic acid (TCA) cycle and electron transport chain (ETC). This altered metabolic state hyperactivates TOR signalling, leading to excessive protein synthesis, disrupted endosomal trafficking, and impaired germ cell fate determination. Importantly, we show that these defects are reversible. Targeted interventions—including inhibition of FAO or TOR signalling, attenuation of protein synthesis, or dietary protein adjustment—restore cellular homeostasis and rescue oogenic defects. The findings from this study reveal a previously unrecognised link between lipid metabolism, nutrient-sensing pathways, and reproductive development. By defining ACC as a central coordinator of metabolic and signalling networks in oogenesis, this work advances fundamental understanding of how energy metabolism shapes reproductive outcomes. Furthermore, the identification of corrective strategies highlights potential therapeutic avenues for addressing infertility and reproductive disorders associated with metabolic imbalance.