Cellular Atlases of Ovarian Microenvironment Alterations by Diet and Genetically-induced Obesity

Obesity, which can arise from genetic or environmental factors, has been shown to cause serious damages to the reproductive system. The ovary, as one of the primary regulators of female fertility, is a complex organ comprised of heterogeneous cell types that work together to maintain a normal ovarian microenvironment (OME). Despite its importance, the effect of obesity on the entire ovary remains poorly documented. In this study, we performed ovary single-cell and nanoscale spatial RNA sequencing to investigate how the OME changed under different kinds of obesity, including high-fat diet (HFD) induced obesity and Leptin ablation induced obesity (OB). Our results demonstrate that OB, but not HFD, dramatically altered the proportion of ovarian granulosa cells, theca-interstitial cells, luteal cells, and endothelial cells. Furthermore, based on the spatial dynamics of follicular development, we defined four subpopulations of granulosa cell and found that obesity drastically disrupted the differentiation of mural granulosa cells from small to large antral follicles. Functionally, HFD enhanced follicle-stimulating hormone (FSH) sensitivity and hormone conversion, while OB caused decreased sensitivity, inadequate steroid hormone conversion, and impaired follicular development. These differences can be explained by the differential expression pattern of the transcription factor Foxo1. Overall, our study provides a powerful and high-resolution resource for profiling obesity-induced OME and offers insights into the diverse effects of obesity on female reproductive disorders.