title: Joint MiRNA/mRNA expression profiling reveals changes consistent with development of dysfunctional corpus luteum after weight gain.
abstract: 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.
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, United States of America.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Bradford
authors.affiliation: Department of Biochemistry, University of Colorado School of Medicine, Aurora, CO 80045, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Jones
authors.affiliation: Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Denver, Aurora, CO 80045, United States of America.
authors.forename: Katerina
authors.initials: K
authors.lastname: Kechris
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Chosich
authors.affiliation: The Genome Institute, Washington University School of Medicine, St Louis, MO 63108, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Montague
authors.affiliation: The Genome Institute, Washington University School of Medicine, St Louis, MO 63108, United States of America.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Warren
authors.affiliation: Department of Pathology (Comparative Medicine), Wake Forest University Primate Center, Winston-Salem, NC 27157, United States of America.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: May
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, United States of America.
authors.forename: Zain
authors.initials: Z
authors.lastname: Al-Safi
authors.affiliation: Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, United States of America.
authors.forename: Satu
authors.initials: S
authors.lastname: Kuokkanen
authors.affiliation: Department of Pathology (Comparative Medicine), Wake Forest University Primate Center, Winston-Salem, NC 27157, United States of America.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Appt
authors.affiliation: Department of Obstetrics & Gynecology, University of Colorado School of Medicine, Aurora, CO 80045, United States of America.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Polotsky
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D003338:Corpus Luteum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects*; D005260:Female; D005498:Follicular Phase / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066248:High Fructose Corn Syrup / Q000009:adverse effects*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D058977:Molecular Sequence Annotation; D010060:Ovulation / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D004041:Dietary Fats; D066248:High Fructose Corn Syrup; D035683:MicroRNAs; D012333:RNA, Messenger