title: Obesity-Dependent Increases in Oocyte mRNAs Are Associated With Increases in Proinflammatory Signaling and Gut Microbial Abundance of Lachnospiraceae in Female Mice.
abstract: RNAs stored in the metaphase II-arrested oocyte play important roles in successful embryonic development. Their abundance is defined by transcriptional activity during oocyte growth and selective degradation of transcripts during LH-induced oocyte maturation. Our previous studies demonstrated that mRNA abundance is increased in mature ovulated oocytes collected from obese humans and mice and therefore may contribute to reduced oocyte developmental competence associated with metabolic dysfunction. In the current study mouse models of diet-induced obesity were used to determine whether obesity-dependent increases in proinflammatory signaling regulate ovarian abundance of oocyte-specific mRNAs. The abundance of oocyte-specific Bnc1, Dppa3, and Pou5f1 mRNAs as well as markers of proinflammatory signaling were significantly increased in ovaries of obese compared with lean mice which were depleted of fully grown preovulatory follicles. Chromatin-immunoprecipitation analyses also demonstrated increased association of phosphorylated signal transducer and activator of transcription 3 with the Pou5f1 promoter in ovaries of obese mice suggesting that proinflammatory signaling regulates transcription of this gene in the oocyte. The cecum microbial content of lean and obese female mice was subsequently examined to identify potential relationships between microbial composition and proinflammatory signaling in the ovary. Multivariate Association with Linear Models identified significant positive correlations between cecum abundance of the bacterial family Lachnospiraceae and ovarian abundance of Tnfa as well as Dppa3, Bnc1, and Pou5f1 mRNAs. Together, these data suggest that diet-induced changes in gut microbial composition may be contributing to ovarian inflammation which in turn alters ovarian gene expression and ultimately contributes to obesity-dependent reduction in oocyte quality and development of infertility in obese patients.
authors.affiliation: Department of Animal Science (F.X., K.R.T., S.G.K., S.C.F., J.R.W.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908; School of Biological Sciences (C.L.A., S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0118; and Food Science and Technology Department (S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0919.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Animal Science (F.X., K.R.T., S.G.K., S.C.F., J.R.W.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908; School of Biological Sciences (C.L.A., S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0118; and Food Science and Technology Department (S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0919.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Anderson
authors.affiliation: Department of Animal Science (F.X., K.R.T., S.G.K., S.C.F., J.R.W.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908; School of Biological Sciences (C.L.A., S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0118; and Food Science and Technology Department (S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0919.
authors.forename: Kelsey R
authors.initials: KR
authors.lastname: Timme
authors.affiliation: Department of Animal Science (F.X., K.R.T., S.G.K., S.C.F., J.R.W.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908; School of Biological Sciences (C.L.A., S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0118; and Food Science and Technology Department (S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0919.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Kurz
authors.affiliation: Department of Animal Science (F.X., K.R.T., S.G.K., S.C.F., J.R.W.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908; School of Biological Sciences (C.L.A., S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0118; and Food Science and Technology Department (S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0919.
authors.forename: Samodha C
authors.initials: SC
authors.lastname: Fernando
authors.affiliation: Department of Animal Science (F.X., K.R.T., S.G.K., S.C.F., J.R.W.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0908; School of Biological Sciences (C.L.A., S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0118; and Food Science and Technology Department (S.C.F.), University of Nebraska-Lincoln, Lincoln, Nebraska 68583-0919.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Wood
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002868:Chromosomal Proteins, Non-Histone; D000068016:Eubacteriales / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004064:Digestive System / Q000382:microbiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000254:growth & development / Q000378:metabolism*; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C511595:Bnc1 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C462180:Dppa3 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha