Obese women exhibit decreased fertility, high
miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that
weight gain induces alterations in CL gene expression.
RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (Chlorocebus aethiops) during
weight gain. 10 months of high-fat, high-
fructose diet (HFHF) resulted in a 20%
weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7-9 based on follicular phase
estradiol peak. 432 mRNAs and 9
miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex
steroid production in human granulosa cells, were up-regulated. Using integrated
miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated
mRNA targets corresponding to opposite changes in
miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex
steroid production characteristic of obese women.
MiRNAs may represent novel
biomarkers of
obesity-related
subfertility and potential new avenues for therapeutic intervention.