title: Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism.
abstract: It's known that blood leptin level is reduced in intrauterine growth retardation (IUGR) fetus, and placental leptin is the major source of fetal blood leptin. This study aimed to investigate the decreased fetal blood leptin level by prenatal caffeine exposure (PCE) and its underlying placental mechanisms. Pregnant Wistar rats were intragastrically administered caffeine (30-120 mg/kg day) from gestational day 9 to 20. The level of fetal serum leptin and the expression of placental leptin-related genes were analyzed. Furthermore, we investigated the molecular mechanism of the reduced placental leptin's expression by treatment with caffeine (0.8-20 μM) in the BeWo cells. In vivo, PCE significantly decreased fetal serum leptin level in caffeine dose-dependent manner. Meanwhile, placental mRNA expression of adenosine A2a receptor (Adora2a), cAMP-response element binding protein (CREB), a short-type leptin receptor (Ob-Ra) and leptin was reduced in the PCE groups. In vitro, caffeine significantly decreased the mRNA expression of leptin, CREB and ADORA2A in concentration and time-dependent manners. The addition of ADORA2A agonist or adenylyl cyclase (AC) agonist reversed the inhibition of leptin expression induced by caffeine. PCE induced a lower level of fetal blood leptin, which the primary mechanism is that caffeine inhibited antagonized Adora2a and AC activities to decreased cAMP synthesis, thus inhibited the expression of the transcription factor CREB and target gene leptin in the placenta. Meantime, the reduced transportation of maternal leptin by placental Ob-Ra also contributed to the reduced fetal blood leptin. Together, PCE decreased fetal blood leptin mainly via reducing the expression and transportation of leptin in the placenta.
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
authors.forename: Yi-Meng
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Han-Wen
authors.initials: HW
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Kou
authors.affiliation: Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Yin-Xian
authors.initials: YX
authors.lastname: Wen
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
authors.forename: Lang
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
authors.forename: Ling-Guo
authors.initials: LG
authors.lastname: Pei
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
authors.forename: Yuan-Zhen
authors.initials: YZ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China. Electronic address: wanghui19@whu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000009:adverse effects*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D047109:Fetal Development / Q000187:drug effects; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000473:pathology; D005333:Fetus / Q000187:drug effects; D006801:Humans; D020738:Leptin / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D010920:Placenta / Q000187:drug effects*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D020738:Leptin; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D054411:Receptors, Leptin; D005576:Colforsin; D002110:Caffeine; D000262:Adenylyl Cyclases
keywords: Adenosine A2a receptor (ADORA2A),; Intrauterine growth retardation (IUGR);; Leptin;; Placenta;; Pregnancy caffeine exposure;; Transportation