title: CMKLR1 deficiency maintains ovarian steroid production in mice treated chronically with dihydrotestosterone.
abstract: Elevated serum chemerin levels correlate with increased severity of polycystic ovary syndrome (PCOS). However, the role of CMKLR1 signaling in ovarian biology under conditions of excess DHT remains unclear. In this study we compared the effects of continuous 90-day high dose DHT exposure (83.3 □g/day) on wild type and CMKLR1-deficient mice. DHT induced PCOS-like clinical signs in wild type mice as well as significant changes in the expression of hormone receptors, steroid synthesis enzymes, and BMPs and their receptors. In contrast, CMKLR1-deficient mice significantly attenuated DHT-induced clinical signs of PCOS and alterations in ovarian gene expression. To determine whether the BMP4 signaling pathway was involved in the pathogenic effects of CMKLR1 signaling in DHT-induced ovarian steroidogenesis, antral follicles were isolated from wild type and CMKLR1 knockout (KO) mice and treated in vitro with combinations of hCG, DHT, and BMP4 inhibitors. BMP4 inhibition attenuated the induction effects of hCG and DHT on estrogen and progesterone secretion in CMKLR1 KO mice, but not in WT mice, implicating the BMP4 signaling pathway in the CMKLR1-dependent response to DHT. In conclusion, CMKLR1 gene deletion attenuates the effects of chronic DHT treatment on ovarian function in experimental PCOS, likely via BMP4 signaling.
authors.affiliation: College of Veterinary Medicine, Northwest Sci-Tech University of A&F, Yangling, Shanxi, 712100, China.|Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Tang
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Huang
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.|University of Science and Technology of China, An-Hui, He-Fei, 230026, China.
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Wang
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Pei-Gen
authors.initials: PG
authors.lastname: Ren
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Tian-Xia
authors.initials: TX
authors.lastname: Xiao
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Bao-Bei
authors.initials: BB
authors.lastname: Wang
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Yan-Fei
authors.initials: YF
authors.lastname: Pan
authors.affiliation: Department of Obstetrics &Gynaecology, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada.|Chronic Disease Program, Ottawa Hospital Research Institute Ontario K1H 8L6, Canada.|Department of Cellular &Molecular Medicine, University of Ottawa; Ottawa, Ontario K1H 8L6, Canada.|Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Ontario K1H 8L6, Canada.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
authors.affiliation: Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Zabel
authors.affiliation: College of Veterinary Medicine, Northwest Sci-Tech University of A&F, Yangling, Shanxi, 712100, China.
authors.forename: Bao-Hua
authors.initials: BH
authors.lastname: Ma
authors.affiliation: College of Veterinary Medicine, Northwest Sci-Tech University of A&F, Yangling, Shanxi, 712100, China.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Zhao
authors.affiliation: Research Laboratory for Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
authors.forename: Jian V
authors.initials: JV
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D013196:Dihydrotestosterone / Q000378:metabolism* / Q000494:pharmacology; D030762:Estrous Cycle; D005260:Female; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011085:Polycystic Ovary Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency*; D011987:Receptors, Steroid / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis* / Q000097:blood
chemical_list: C486456:CMKLR1 protein, mouse; D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; D013256:Steroids; D013196:Dihydrotestosterone