In perinatal medicine,intrauterine growth restriction(IUGR)is one of the greatest challenges.The etiology of IUGR is multifactorial,but most cases are thought to arise from placental insufficiency.However,identifying ...In perinatal medicine,intrauterine growth restriction(IUGR)is one of the greatest challenges.The etiology of IUGR is multifactorial,but most cases are thought to arise from placental insufficiency.However,identifying the placental cause of IUGR can be difficult due to numerous confounding factors.Selective IUGR(sIUGR)would be a good model to investigate how impaired placentation affects fetal development,as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors.Herein,we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins.Specifically,we identified a total of 5481 proteins,of which 233 were differentially expressed(57 up-regulated and 176 down-regulated)in IUGR twins.Bioinformatics analysis indicates that these differentially expressed proteins(DEPs)are mainly associated with cardiovascular system development and function,organismal survival,and organismal development.Notably,34 DEPs are significantly enriched in angiogenesis,and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed.Moreover,we found decreased expression of metadherin(MTDH)in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro.Collectively,our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins,and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.展开更多
Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substan...Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.81971399 and 82171661).
文摘In perinatal medicine,intrauterine growth restriction(IUGR)is one of the greatest challenges.The etiology of IUGR is multifactorial,but most cases are thought to arise from placental insufficiency.However,identifying the placental cause of IUGR can be difficult due to numerous confounding factors.Selective IUGR(sIUGR)would be a good model to investigate how impaired placentation affects fetal development,as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors.Herein,we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins.Specifically,we identified a total of 5481 proteins,of which 233 were differentially expressed(57 up-regulated and 176 down-regulated)in IUGR twins.Bioinformatics analysis indicates that these differentially expressed proteins(DEPs)are mainly associated with cardiovascular system development and function,organismal survival,and organismal development.Notably,34 DEPs are significantly enriched in angiogenesis,and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed.Moreover,we found decreased expression of metadherin(MTDH)in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro.Collectively,our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins,and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.
基金supported by the National Natural Science Foundation of China(No.82001651 and No.81660268).
文摘Objective Intrauterine growth restriction followed by postnatal catch-up growth(CG-IUGR)increases the risk of insulin resistance-related diseases.Low-density lipoprotein receptor-related protein 6(LRP6)plays a substantial role in glucose metabolism.However,whether LRP6 is involved in the insulin resistance of CG-IUGR is unclear.This study aimed to explore the role of LRP6 in insulin signaling in response to CG-IUGR.Methods The CG-IUGR rat model was established via a maternal gestational nutritional restriction followed by postnatal litter size reduction.The mRNA and protein expression of the components in the insulin pathway,LRP6/β-catenin and mammalian target of rapamycin(mTOR)/S6 kinase(S6K)signaling,was determined.Liver tissues were immunostained for the expression of LRP6 andβ-catenin.LRP6 was overexpressed or silenced in primary hepatocytes to explore its role in insulin signaling.Results Compared with the control rats,CG-IUGR rats showed higher homeostasis model assessment for insulin resistance(HOMA-IR)index and fasting insulin level,decreased insulin signaling,reduced mTOR/S6K/insulin receptor substrate-1(IRS-1)serine307 activity,and decreased LRP6/β-catenin in the liver tissue.The knockdown of LRP6 in hepatocytes from appropriate-for-gestational-age(AGA)rats led to reductions in insulin receptor(IR)signaling and mTOR/S6K/IRS-1 serine307 activity.In contrast,LRP6 overexpression in hepatocytes of CG-IUGR rats resulted in elevated IR signaling and mTOR/S6K/IRS-1 serine307 activity.Conclusion LRP6 regulated the insulin signaling in the CG-IUGR rats via two distinct pathways,IR and mTOR-S6K signaling.LRP6 may be a potential therapeutic target for insulin resistance in CG-IUGR individuals.
