Glycogen metabolism in mouse embryonic Sertoli cells sustains the germ line through the lactate shuttle

Abstract

Metabolites are key regulators of cell fate decisions, epigenetic remodeling, and lineage commitment. While genetic pathways governing testis differentiation are well studied, the role of metabolism remains poorly understood. In this study, we investigated a transient, male-specific accumulation of glycogen in supporting (Sertoli) cells of embryonic testis in mice. Although glycogen metabolism was dispensable for Sertoli cell differentiation, its disruption led to reduced lactate production and impaired PGCs ability to colonize the newly forming testis cords. Inhibiting lactate transport further revealed a critical metabolic coupling between Sertoli and germ cells during early testis development. Surprisingly, external lactate or glucose supplementation failed to rescue the germ cell phenotype. These findings suggest that glycogen accumulation supports a critical developmental window in which both Sertoli and germ cells are metabolically constrained and unable to rely on external carbon sources. This highlights a sensitive period during testicular development where nutrient scarcity could have long-term consequences for fertility.