Multi-omics analysis reveals IGF1 as a central regulator of Sertoli cell proliferation and metabolic reprogramming in Tibetan sheep

Huihui Wang¹Xujie Li¹Xingcai Qi¹Xiaodan Shi¹Baoqi He¹Chen Haolin²Youji Ma¹Taotao Li^1*

• ¹Gansu Agricultural University, Lanzhou, China
• ²Guizhou Academy of Agricultural Sciences, Guiyang, China

Insulin-like growth factor 1 (IGF1) is essential for cellular development and testicular function. Tibetan sheep, as an important high-altitude adapted livestock species, provide a unique model to explore reproductive mechanisms under hypoxic conditions, yet the cell-intrinsic actions of IGF1 in this species remain unclear. Using integrated approaches including transcriptomic and metabolomic profiling alongside functional assays, we demonstrate that IGF1 overexpression promotes Sertoli cell proliferation and inhibits apoptosis, while its knockdown induces opposite effects. Transcriptomic analysis revealed enrichment of genes involved in cell cycle, DNA replication, glycolysis, and HIF-1 signaling. Gene set enrichment analysis further confirmed activation of mitosis and the pentose phosphate pathway. Metabolomic profiling indicated upregulation of nucleotide and purine metabolism. Integrated analysis showed that IGF1 synchronously enhances glycolysis, the pentose phosphate pathway, the TCA cycle, and nucleotide biosynthesis, providing energy and biosynthetic precursors for proliferation. These findings establish IGF1 as a key regulator that reprograms Tibetan sheep Sertoli cells into a proliferative and metabolically active state in vitro, providing mechanistic insight into IGF1-driven reproductive regulation in a high-altitude-adapted livestock species and a foundation for future studies on reproductive adaptation to hypoxia.