Obesity alters the mouse endometrial transcriptome in a cell context-dependent manner

Abstract

Obesity impacts fertility and is positively correlated with endometrial hyperplasia and endometrial cancer occurrence. Endometrial epithelia often harbor disease driver-mutations, while endometrial stroma are highly regulative of neighboring epithelia. Here, we sought to determine distinct transcriptome changes occurring in individual cell types in the obese mouse uterus. Outbred CD-1 mice were fed high-fat or control diets for 18 weeks, estrous cycle staged, and endometrial epithelia, macrophages, and stroma isolated for transcriptomic analysis. High-fat diet mice displayed increased body mass and developed glucose intolerance, hyperinsulinemia, and fatty liver. Obese mouse epithelia displayed differential gene expression for genes related to innate immunity and leukocyte chemotaxis. The obese mouse stroma differentially expressed factors related to circadian rhythm, and expression of these genes correlated with glucose tolerance or body mass. We observed correlations between F4/80 + macrophage numbers, Cleaved Caspase 3 (CC3) apoptosis marker staining and glucose intolerance among obese mice, including a subgroup of obese mice with high CC3 + luminal epithelia. This subgroup displayed differential gene expression among all cell types, with pathways related to immune escape in epithelia and macrophages, while the stroma dysregulated pathways related to regulation of epithelia. These results suggest an important role for differential response of both the epithelia and stroma in their response to obesity, while macrophages are dysregulated in the context of apoptotic epithelia. The obesity-related gene expression programs in cells within the uterine microenvironment may influence the ability of the endometrium to function during pregnancy and influence disease pathogenesis.

PIK3CA mutation in endometriotic epithelial cells promotes viperin-dependent inflammatory response to insulin

“…Hallmark pathways and Gene Ontology Biological Processes (GOBP) gene sets were retrieved from MSigDB [ 36 ]. ClusterProfiler [ 37 ] was used to compute and visualize pathway enrichment of GOBP gene sets to respective gene universes, detailing the significance of the enrichment and number of genes involved previously described [ 38 – 41 ]. eulerr [ 42 ] was used to produce proportional Euler diagrams.…”

The Molecular Link between Obesity and the Endometrial Environment: A Starting Point for Female Infertility

“…In this context, currently, many transcriptomic analyses of genes linked to embryonic implantation and endometrial proliferation are performed via the endometrial receptivity assay (ERA), or ER Map, a useful commercially available molecular tool able to evaluate the receptivity of the human endometrium [11]. Overall, the existing literature sustains that obese women may exhibit differential gene expression in the endometrium in association with endometrial cancer [12] and angiogenesis [13], as well as an inflammatory response and decidualization [14], highlighting the importance of this kind of investigation to better comprehend the receptivity and, potentially, embryo implantation. To date, not all contributing factors able to interfere with endometrial receptivity are well known, but, apart from inflammatory events, they are often associated with endocrine causes, thin endometria, polyps, septa, fibroids, immunologically mediated disturbances, pre-eclampsia [15], cardiovascular risk factors such as dyslipidemia and hypertension, and diabetes [16] contributing to a series of reproductive problems [17].…”