Rab14-Mediated Lipophagy Disrupts Lipid Homeostasis in Granulosa Cells and Impairs Female Fertility.

As health awareness grows, more people are turning to weight loss-yet excessive slimming or dietary imbalance is quietly triggering a wave of fertility problems. Researches show that low BMI or excessive exercise can negatively impact fertility, but its specific cellular mechanism remain unclear. In this study, we investigated how adipose tissue influences ovarian function under energy-restricted conditions by establishing a peri-ovarian adipose tissue (POAT) removal mouse model. We showed that POAT removal resulted in a significant decrease in litter size, impaired follicle development, and an increased apoptosis rate in granulosa cells (GCs). Additionally, the lipid droplets (LDs) content in the ovaries and GCs was significantly reduced. We also observed that Rab14 expression was upregulated in GCs after POAT removal. Functional experiments further showed that Rab14 overexpression significantly enhanced lipophagy activity, reduced the number and volume of LDs, and inhibited the expression of lipid droplet protein PLIN2. Meanwhile, Rab14 overexpression inhibited the phosphorylation level of AKT and induced the apoptosis of granulosa cells, suggesting that Rab14 may activate the cell death pathway mediated by lipophagy. Taken together, POAT may support ovarian function by maintaining lipid homeostasis within GCs. The role of Rab14 in the regulation of lipophagy may link local adipose-derived signaling with GCs survival and female fertility.