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

Area of Science:

• Reproductive Biology
• Metabolic Disease Research
• Genomics and Transcriptomics

Background:

• Obesity is linked to infertility, endometrial hyperplasia, and cancer.
• Endometrial epithelia can harbor mutations, while stroma regulate epithelial function.
• Understanding cell-specific changes in the obese uterus is crucial for reproductive health and disease pathogenesis.

Purpose of the Study:

• To investigate distinct transcriptome alterations in endometrial epithelial, stromal, and macrophage cells of obese mice.
• To correlate obesity-induced metabolic changes with uterine cell-specific gene expression patterns.
• To identify cellular mechanisms underlying obesity's impact on the uterine microenvironment.

Main Methods:

• Outbred CD-1 mice were fed high-fat or control diets for 18 weeks.
• Mice were estrous cycle staged, and endometrial epithelia, macrophages, and stroma were isolated.
• Transcriptomic analysis was performed on isolated cell populations.

Main Results:

• Obese mice exhibited increased body mass, glucose intolerance, hyperinsulinemia, and fatty liver.
• Obese mouse epithelia showed differential gene expression in innate immunity and leukocyte chemotaxis pathways.
• Obese mouse stroma differentially expressed circadian rhythm-related genes, correlating with metabolic parameters.
• A subgroup of obese mice with high epithelial apoptosis displayed immune escape pathways in epithelia/macrophages and dysregulated epithelial regulation in stroma.

Conclusions:

• Obesity induces distinct transcriptomic responses in endometrial epithelial and stromal cells.
• Macrophages are dysregulated in obese mice with apoptotic epithelia.
• Obesity-related gene expression programs in the uterine microenvironment may affect pregnancy function and disease pathogenesis.