Decreased gremlin 1 expression in women with body mass index ≥35 kg/m² is mediated by interleukin 10 and interleukin 1β in the follicular fluid

Objective: To determine how body mass index (BMI) affects the follicular fluid cytokine milieu and to investigate how this inflammatory environment impacts cumulus cell signaling. Design: Experimental study. Setting: Tertiary hospital–based research laboratory. Patient(s): Women with normal (18.5–24.9 kg/m², n = 35) and obese (35–42 kg/m², n = 11) BMI undergoing controlled ovarian stimulation for intracytoplasmic sperm injection (ICSI). Intervention(s): Cumulus cell treatment with obese follicular fluid, interleukin (IL)-10, and IL-1β. Cumulus cell gene expression and protein levels were compared with and without treatment and included 5 to 7 women per group for each experiment. Main outcome measure(s): Follicular fluid cytokine concentrations between normal and obese women were compared using multiplex bead assay. Differential cumulus cell gene expression of GREM1, HAS2, PTGS2, and VCAN were measured by quantitative reverse polymerase chain reaction (RT-qPCR), and protein levels were determined by flow cytometry and confocal microscopy. Results: Compared to women with normal BMI, women with BMI ≥35 kg/m² undergoing ICSI had higher follicular concentrations of IL-10 (9.46 pg/mL [0.59–19.16] vs. 53.39 pg/mL [14.97–236.37]) and IL-1β (1.92 pg/mL [1.92–5.18] vs. 5.18 pg/mL [1.92–16.33]), as well as decreased relative cumulus cell expression of GREM1 (1.01 [0.66–1.40] vs. 0.51 [0.38–0.74]), a surrogate marker of positive ICSI outcomes. Furthermore, elevated IL-10 and IL-1β appear to be responsible for decreasing GREM1 expression in women with BMI ≥35 kg/m². Conclusion: Our findings suggest that follicular inflammation associated with obesity affects cumulus cell signaling. At a molecular level, derangements to the immune system resulting in decreased GREM1 expression may be a partial explanation for the suboptimal ICSI outcomes observed with obesity.