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

Original Articles: Gamete Biology

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VOLUME 1, ISSUE 1, P16-26

Authors:

Tana Kim, M.D., Yohan Kim, Ph.D., Fabrice Lucien, Ph.D., Yulian Zhao, M.D., Ph.D., Elizabeth Ann L. Enninga, Ph.D.

Abstract:

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.

Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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