The PI3K-AKT-mTOR pathway maintains germ cell survival in obese mice by regulating stress granule assembly

Abstract Obesity is a well-recognized risk factor for male infertility by disrupting spermatogenesis. However, in the testicular microenvironment of obese individuals, a subset of spermatogenic cells can still survive normally and differentiate into mature sperm. our study demonstrated that inguinal fat accumulation-induced testicular hyperthermia activates the PI3K-AKT signaling pathway. This pathway plays a pivotal role in cell growth, proliferation, and survival. Its activation leads to reduced expression of tumor suppressor genes TSC1/TSC2, which are negative regulators of mTORC1. Subsequent mTORC1 activation further promoted the formation of stress granules (SGs). Critically, these SGs recruit RACK1, a key component of the MAPK signaling pathway, thereby blocking apoptotic pathways in spermatogenic cells.This anti-apoptotic effect enabled the protected subset of germ cells to survive and differentiate into mature sperm despite the adverse testicular microenvironment in obesity.​ In conclusion, obesity plays a critical role in male infertility through multiple mechanisms that disrupt spermatogenesis.However, a subset of spermatogenic cells survives via activation of the PI3K-AKT pathway, SG formation, and suppression of apoptosis. This discovery provides novel insights and potential therapeutic targets for obesity-associated male infertility.