Paternal high-fat diet enhances offspring whole-body insulin sensitivity and skeletal muscle insulin signaling early in life.
Physiological reports
Evidence suggests that paternal diet can predispose offspring to metabolic dysfunction. Despite this knowledge, little is known regarding the effects of paternal high-fat feeding on offspring insulin sensitivity. The purpose of this study was to investigate for the first time the effects of paternal high-fat feeding on whole-body and skeletal muscle insulin action in young and adult offspring. At 4 weeks of age, founder C57BL6/N males (F0) were fed a high-fat diet or control diet for 12 weeks and then bred with females on a control diet. Offspring (F1) were euthanized at 6 weeks, 6 months, or 12 months and insulin-stimulated insulin signaling was measured ex vivo in isolated soleus muscle. At 6 weeks of age, paternal high fat offspring (HFO) had enhanced whole-body insulin sensitivity (35%, P < 0.05), as well as, increased insulin-stimulated skeletal muscle phosphorylation of Akt threonine 308 (70%, P < 0.05) and AS160 threonine 642 (80%, P < 0.05) compared to paternal control fed offspring (CFO), despite both offspring groups consuming standard chow. At 6 months of age, HFO had increased percent body fat compared to CFO (74%, P < 0.005) and whole-body and skeletal muscle insulin signaling normalized to CFO. Body fat was inversely related with insulin signaling in HFO, but not CFO. These findings suggest that paternal high-fat feeding contributes to enhanced whole-body and skeletal muscle insulin sensitivity in HFO early in life; however, these benefits are lost by early adulthood, potentially due to premature increases in body fat.
10.14814/phy2.13583
Father's obesity programs the adipose tissue in the offspring via the local renin-angiotensin system and MAPKs pathways, especially in adult male mice.
Ornellas Fernanda,Bringhenti Isabele,Mattos Brenda Akemi N F,Mandarim-de-Lacerda Carlos Alberto,Aguila Marcia Barbosa
European journal of nutrition
PURPOSE:Studies demonstrated the influence of mother's obesity on offspring. However, the father is also related to programming the future generation. The study aimed to evaluate the effects of father's obesity upon white adipose tissue (WAT) remodeling, resulting in activation of signaling pathways and inflammation in male and female offspring. METHODS:Male C57BL/6 mice received control diet (lean father group; 17% energy from lipids) or high-fat diet (obese father group; 49% energy from lipids) for 8 weeks before mating. The mothers received control diet throughout the experiment. Mice were mated: lean mother and lean father, and lean mother and obese father. Offspring received control diet from weaning until 3 months of age when they were studied. RESULTS:In the offspring, father's obesity led to decreased QUICKI with impairment of the insulin signaling pathway in both sexes. In line with these findings, in white adipose tissue, male offspring demonstrated hypertrophied adipocytes, enhanced proinflammatory cytokines, overactivation of components of the local renin-angiotensin system (RAS) and extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of peroxisome proliferator-activated receptors (alpha and gamma). CONCLUSIONS:We observed that father's obesity influences the offspring in adult life, with an impairment in insulin homeostasis, adipocyte remodeling, and adipose tissue overexpression of IL-6 and TNF-alpha in male offspring. The activation of local RAS and ERK1/2, a concomitant PPAR diminishing, and impairment in phosphorylation of AKT and IRS-1 could explain at least in part the findings regardless of the increase in body mass in the offspring.
10.1007/s00394-017-1473-4
Maternal exercise attenuates the lower skeletal muscle glucose uptake and insulin secretion caused by paternal obesity in female adult rat offspring.
Falcão-Tebas Filippe,Marin Evelyn C,Kuang Jujiao,Bishop David J,McConell Glenn K
The Journal of physiology
KEY POINTS:Paternal obesity negatively influences metabolic outcomes in adult rat offspring. Maternal voluntary physical activity has previously been reported to improve glucose metabolism in adult rat offspring sired by healthy fathers. Here, we investigated whether a structured programme of maternal exercise training before and during gestation can attenuate the negative impacts that paternal obesity has on insulin sensitivity and secretion in female adult offspring. Exercise before and during pregnancy normalised the lower insulin sensitivity in skeletal muscle and the lower insulin secretion observed in female offspring sired by obese fathers. This paper presents a feasible, low-cost and translatable intervention strategy that can be applied perinatally to support multifactor interventions to break the cycle of metabolic dysfunction caused by paternal obesity. ABSTRACT:We investigated whether maternal exercise before and during gestation could attenuate the negative metabolic effects of paternal high-fat diet-induced obesity in female adult rat offspring. Fathers consumed a normal chow or high-fat diet before mating. Mothers exercised on a treadmill before and during gestation or remained sedentary. In adulthood, female offspring were assessed using intraperitoneal insulin and glucose tolerance tests (IPITT and IPGTT, respectively), pancreatic morphology, ex vivo skeletal muscle insulin-stimulated glucose uptake and mitochondrial respiratory function. Paternal obesity impaired whole-body and skeletal muscle insulin sensitivity and insulin secretion in adult offspring. Maternal exercise attenuated the lower insulin-stimulated glucose uptake in offspring sired by obese fathers but distal insulin signalling components (p-AKT Thr308 and Ser473, p-TBC1D4 Thr642 and GLUT4) remained unchanged (P > 0.05). Maternal exercise increased citrate synthase activity only in offspring sired by obese fathers. Maternal exercise also reversed the lower insulin secretion in vivo observed in offspring of obese fathers, probably due to an attenuation of the decrease in pancreatic beta cell mass. In summary, maternal exercise before and during pregnancy in rats attenuated skeletal muscle insulin resistance and attenuated the decrease in pancreatic beta cell mass and insulin secretion observed in the female offspring of obese fathers.
10.1113/JP279582
The Differentiation Potency of Trophoblast Stem Cells from Mouse Androgenetic Embryos.
Suzuki Daisuke,Morimoto Hiromu,Yoshimura Kaoru,Kono Tomohiro,Ogawa Hidehiko
Stem cells and development
In mice, trophoblast stem (TS) cells are derived from the polar trophectoderm of blastocysts. TS cells cultured in the presence of fibroblast growth factor 4 (Fgf4) are in an undifferentiated state and express undifferentiated marker genes such as Cdx2. After removing Fgf4 from the culture medium, TS cells drastically reduce the expression of undifferentiated marker genes, stop cell proliferation, and differentiate into all trophoblast cell subtypes. To clarify the roles of the parental genomes in placentation, we previously established TS cells from androgenetic embryos (AGTS cells). AGTS cells are in the undifferentiated state when cultured with Fgf4 and express undifferentiated marker genes. After removing Fgf4, AGTS cells differentiate into trophoblast giant cells (TGCs), but not into spongiotrophoblast cells, and some of the AGTS cells continue to proliferate. In this study, we investigated the differentiation potency of AGTS cells by analyzing the expression of undifferentiated marker genes and all trophoblast cell subtype-specific genes. After removing Fgf4, some undifferentiated marker genes (Cdx2, Eomes and Elf5) continued to be expressed. Interestingly, TGCs differentiated from AGTS cells also expressed Cdx2, but not Prl3d1. Moreover, the expression of Gcm1 and Synb was induced after the differentiation, indicating that AGTS cells preferentially differentiated into labyrinth progenitor cells. Cdx2 knockdown resulted in increased Prl3d1 expression, suggesting that Fgf4-independent Cdx2 expression inhibited the functional TGCs. Moreover, Fgf4-independent Cdx2 expression was activated by Gab1, one of the paternally expressed imprinted genes via the mitogen-activated protein kinase kinase (MEK)-extracellular signal regulated protein kinase (ERK) pathway. These results suggested that the paternal genome activates the MEK-ERK pathway without the Fgf4 signal, accelerates the differentiation into labyrinth progenitor cells and controls the function of TGCs.
10.1089/scd.2018.0068
Paternal high-fat diet and exercise regulate sperm miRNA and histone methylation to modify placental inflammation, nutrient transporter mRNA expression and fetal weight in a sex-dependent manner.
Claycombe-Larson Kate G,Bundy Amy N,Roemmich James N
The Journal of nutritional biochemistry
We previously have shown that male offspring (F1) of fathers (F0) fed a high-fat (HF) diet and that exercised had greater skeletal muscle insulin signaling and reduced type 2 diabetes mellitus (T2DM) risk compared to fathers fed HF diet and that remained sedentary. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by alterations in placental tissue growth via changes in sperm miRNA expression. To test these hypotheses, 3-week-old male C57BL/6 mice were fed a normal-fat diet (16% fat) or an HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months. Results showed that F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of dimethylated histone 3 lysine 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males. Placental interleukin-1β and tumor necrosis factor (TNF)-α mRNA expression was reduced by paternal exercise, while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. Treatment of primary placental cell with miRNA 193b inhibited TNF-α mRNA expression, and treatment of TNF-α decreased SLC38a2 mRNA expression. Moreover, paternal exercise increased body weight at weaning in a female offspring. These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise, while placental inflammatory gene expression is influenced by paternal exercise in offspring in a sex-specific manner.
10.1016/j.jnutbio.2020.108373
Modulation of Bax expression in physiological and pathological human placentas throughout pregnancy.
Cobellis Luigi,De Falco Maria,Torella Marco,Trabucco Elisabetta,Caprio Francesca,Federico Elisabetta,Manente Lucrezia,Coppola Gabriele,Laforgia Vincenza,Cassandro Roberto,Colacurci Nicola,De Luca Antonio
In vivo (Athens, Greece)
Apoptosis is intimately involved in placental homeostasis, growth and remodelling, and apoptotic rates increase progressively during normal pregnancy as part of normal placental development. Moreover, apoptosis increases in pregnancies complicated by some pathologies such as preeclampsia, fetal growth restriction and diabetes. In the present study, we describe differences in the expression of proapoptotic protein Bax, in first trimester voluntary termination of pregnancy, first trimester abortion (reserved abortion), caesarean birth, spontaneous birth, preeclampsia and diabetes. We first observed a strong increase of Bax expression in the cytotrophoblast, stroma, endothelial cells and decidua of placentas of the first trimester abortion compared to the low/moderate Bax immunopositivity in all the placental compartments during the first trimester voluntary termination of pregnancy. Secondly, we showed a more intense immunopositivity for Bax in the third trimester spontaneous birth with respect to the third trimester caesarean birth. Thirdly, we observed an increase of Bax expression in preeclamptic placentas compared to the normal full-term placentas. In contrast, we observed a moderate Bax expression in diabetic placentas only slightly lower than the normal full-term placentas. Our results seem to suggest that deregulation of apoptotic turnover may lead to placental dysfunction and pathologies.
[Expression of lectin-liked oxidized low density lipoprotein receptor-1 and apoptosis associated genes in placenta and the relationship thereof with morbility of early-onset preeclampsia].
Meng Tao,Chen Hai-Ying,Li Jun,Shang Tao
Zhonghua yi xue za zhi
OBJECTIVE:To investigate the expression of lectin-liked oxidized low density lipoprotein receptor-1 (LOX-1) and apoptosis associated genes: caspase-3, Bax, and Bcl-2, in placenta and the relationship thereof with the morbility of early-onset preeclampsia. METHODS:30 placentas of normal pregnant women at the 21+1 to 32 weeks gestation, 30 patients with early-onset preeclampsia at the 21+1 to 32 weeks gestation, 30 normal pregnant women at the 32+ weeks gestation to full term, and 30 patients with late-onset preeclampsia at the 32+ weeks gestation to full term. Immunohistochemistry, RT-PCR, and Western-blotting were used to detect the expression of LOX-1, caspase-3, Bax, and Bcl-2 in the placenta. RESULTS:The LOX-1 protein expression levels (grey levels) in the placenta tissues at 20W(+1) - 24W, 24W(+1) - 28W, and 28W(+1) - 32W gestation of the early-onset preeclampsia were 27.6 +/- 1.3, 29.4 +/- 1.4, and 32.3 +/- 1.6 respectively, all significantly higher than those of the normal pregnant women (11.2 +/- 0.6, 18.7 +/- 1.0, and 25.5 +/- 1.6 respectively, all P < 0.05). The LOX-1 protein levels at the 32W(+1) - 36W and 36W(+1) - 40W gestation of the late-onset preeclampsia patients were: 29.3 +/- 1.5 and 32.3 +/- 1.3 respectively, not significantly different from those of the normal pregnant women (28.1 +/- 1.8 and 31.3 +/- 1.6 respectively, both P > 0.05). The caspase-3 protein level Caspase-3 protein at 20W(+1) - 24W, 24W(+1) - 28W, and 28W(+1) - 32W gestation of the early-onset preeclampsia patients were 17.4 +/- 0.9, 23.2 +/- 1.1, and 28.4 +/- 0.8 respectively, all significantly higher than those of the normal pregnant women (8.5 +/- 1.0, 11.3 +/- 1.1, and 14.4 +/- 1.2 respectively, all P < 0.05). The caspase-3 protein levels at 32W(+1) - 36W and 36W(+1) - 40W gestation of the late-onset preeclampsia patients were 29.3 +/- 0.5 and 33.3 +/- 1.1 respectively, all significantly higher than those of the normal pregnant women (22.4 +/- 1.5 and 27.2 +/- 1.3 respectively, both P < 0.05). The Bax mRNA expression and protein expression of the early-onset preeclampsia patients were higher than those of the normal pregnant women, and the Bcl-2 mRNA expression and protein expression of the early-onset preeclampsia patients were lower than those of the normal pregnant women. The Bax mRNA expression and protein expression of the late-onset preeclampsia patients were still higher than those of the normal pregnant women; however, the Bcl-2 mRNA expression and protein expression of the late-onset preeclampsia patients were not significantly different from those of the normal pregnant women. CONCLUSION:LOX-1 may be concerned with the pathogenesis of early onset of preeclampsia.
Gene expression patterns of the Bcl-2 and Bax genes in preterm birth.
Demendi Csaba,Börzsönyi Balázs,Végh Veronika,Nagy Zsolt B,Rigó János,Pajor Attila,Joó József Gábor
Acta obstetricia et gynecologica Scandinavica
OBJECTIVE:The apoptotic genes Bax and Bcl-2 are both involved in the pathogenesis of preterm delivery in conjunction with additional factors. We characterized gene expression patterns of these apoptotic regulatory genes as well as relevant environmental factors. DESIGN:A gene expression study with evaluation of clinical data. SETTING:Semmelweis University, Budapest, Hungary. SAMPLE:Human placental samples from 104 preterm and 140 full-term pregnancies. METHODS:Gene tests were performed using real-time PCR to assess gene expression patterns of Bax and Bcl-2 in human placental samples. Clinical data were collected from our computerized database. MAIN OUTCOME MEASURES:Apoptotic gene expression pattern and clinical information against the background of preterm delivery. RESULTS:In placental samples from preterm delivery pregnancies, expression of the Bcl-2 gene was unchanged, whereas the Bax gene was overexpressed. Placental gene expression of Bax in preterm delivery was dependent on gestational age with gestational weeks 28-32 and 32-36 associated with overexpression, and no overexpression in gestational weeks 24-28. Preterm delivery began with premature rupture of membranes in 70.2% and spontaneous uterine activity in 29.8%. CONCLUSIONS:The Bax gene was overexpressed in preterm delivery, whereas expression of the Bcl-2 gene remained unchanged. After the 28(th) gestational week, apoptosis appears to be a key factor in the pathogenesis of preterm delivery.
10.1111/j.1600-0412.2012.01428.x
Bcl-2/Bax protein and mRNA expression in yak (Bos grunniens) placentomes.
Fan JiangFeng,Yu SiJiu,Cui Yan,Xu Gengquan,Wang Libin,Pan Yangyang,He Honghong
Theriogenology
Placental function is complex and influenced by various factors; furthermore, it depends on a delicate balance between cell proliferation, cell differentiation, and cell death. Bcl-2 and Bax proteins are key apoptosis regulators and are considered to play an important role in the maintenance of both dynamic balance and integrity of many tissues. Changes in Bcl-2 and Bax expressions have been described during different developmental stages in normal human placentas. Studies furthermore indicated several pathological placental changes to be related to abnormal Bcl-2 and Bax expressions. In the present study, we investigated both expression and distribution of Bcl-2 and Bax in yak placentas. For this, we collected placentas of 35 yaks at different stages of pregnancy as well as cotyledonary villi of four postpartum yaks. Protein and mRNA expressions of both Bcl-2 and Bax were investigated via immunohistochemistry, Western blot, and real-time PCR. Immunoreactive Bcl-2 protein was mainly localized near the fetal villous trophoblast at various gestational stages and post-partum. The Positive Index (PI) of Bcl-2 protein expression significantly decreased with increasing gestational age. Early during pregnancy (≤2 months), the Bax protein was widely distributed in the fetal villous trophoblast layer, the maternal caruncular crypt epithelium, and the stroma. Subsequently, the Bax protein distribution gradually concentrated in the fetal villous trophoblast layer. The staining intensity of Bax increased from the 3rd month to the prepartum of gestation. The PI reached a minimum of 9.4 ± 2.2 in fetal chorionic villi (FCV) and 1.3 ± 0.8 in maternal caruncular crypts (MCC) of the three months group. Both Bcl-2 and Bax had maximum immunoreactivity in the fetal villous trophoblast layer of placentas collected form postpartum yaks (with PIs of 36.6 ± 5.7 and 38.2 ± 4.8, respectively). Protein and mRNA expression of Bcl-2 and Bax investigated via Western blot and real-time PCR demonstrated similar expression profiles than immunohistochemistry. These results demonstrated the dynamic expression of Bcl-2 and Bax during pregnancy and postpartum in yak placentas. The temporal and spatial expression patterns indicate that Bcl-2 and Bax may participate in physiological processes of the placenta, such as formation, maturation, and antepartum degeneration that are critical for fetal and placental development in yak.
10.1016/j.theriogenology.2017.07.045
Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling.
Knöfler Martin,Pollheimer Jürgen
Frontiers in genetics
Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signaling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signaling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β -catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signaling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signaling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β -catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signaling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodeling. Moreover, changes in Wnt signaling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signaling in physiological and abnormal trophoblast function.
10.3389/fgene.2013.00190
Association of Wnt2 and sFRP4 expression in the third trimester placenta in women with severe preeclampsia.
Zhang Zhan,Zhang Lin,Zhang Linlin,Jia Liting,Wang Peng,Gao Yan
Reproductive sciences (Thousand Oaks, Calif.)
BACKGROUND:The Wnt signaling pathway is a conserved pathway and plays a crucial role in regulating trophoblast functions. Abnormal expression of the Wnt pathway may result in the dysfunction of the trophoblast that can contribute to the pathogenesis of preeclampsia (PE). However, published data regarding the association between Wnt pathway and PE in human pregnancy is rare. OBJECTIVE:The aims of this study were to investigate the expression pattern of Wnt2 and secreted frizzled-related protein 4 (sFRP4) in the third trimester human placenta and to evaluate the relationship between changes in placental Wnt2 and sFRP4 expression and severe PE. METHODS:The expression of Wnt2 and sFRP4 in normal and severe PE placentas was examined using immunohistochemistry (IHC), real-time polymerase chain reaction, and Western blot. RESULTS:Compared to the controls, the relative expression of Wnt2 messenger RNA was remarkably downregulated in the PE placentas, while there was no significant difference in sFRP4 between the 2 groups. The IHC indicated that Wnt2 and sFRP4 were expressed predominantly in the villous syncytiotrophoblast and the extravillous trophoblast, whereas Wnt2 in the control group showed higher staining intensity than in the PE group, and sFRP4 in the PE group had a higher staining intensity than in the control group. Furthermore, the results of the Western blots were consistent with the IHC. CONCLUSIONS:The Wnt signaling pathway was detected in human third trimester placentas, and the decreased placental expression of Wnt2 and increased placental expression of sFRP4 may be associated with the pathogenesis of severe PE.
10.1177/1933719112472740
Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/β-catenin signaling pathway.
Li Ning,Li Shuhong,Wang Yanwei,Wang Jiahui,Wang Kai,Liu Xin,Li Yan,Liu Juan
Cell biology international
WNT2 has been reported to be important for placental development, especially for the proper vascularization of the placenta. However, its precise role in first-trimester trophoblast cells is still unknown. WNT2 expression in the villous tissues of unexplained recurrent spontaneous abortion (URSA) patients was compared with that of healthy women by Western blot. The function of WNT2 in HTR-8/SVneo trophoblast cells was evaluated by altering the cellular WNT2 level through overexpression and shRNA knockdown. The molecular mechanism of the effect of WNT2 on trophoblast cells was investigated. The association of WNT2 with the Wnt/β-catenin signaling pathway was studied through Western blot and immunofluorescence. Results showed that WNT2 protein expression was significantly decreased in villi of the URSA group compared with the control group. In vitro studies showed that WNT2 could promote human trophoblast cell proliferation and migration through activating the Wnt/β-catenin signaling pathway. Moreover, upon the knockdown of WNT2, trophoblast cell proliferation and migration were significantly suppressed. In conclusion, our study indicated that WNT2 plays an important role in trophoblast function. WNT2 insufficiency might cause impaired trophoblast cell proliferation and migration via downregulation of Wnt/β-catenin signaling pathway.
10.1002/cbin.10807
Roles of PPARγ/NF-κB signaling pathway in the pathogenesis of intrahepatic cholestasis of pregnancy.
Zhang Yan,Hu Lingqing,Cui Yan,Qi Zhigang,Huang Xiaoping,Cai Liyi,Zhang Ting,Yin Yongxiang,Lu Zhiyi,Xiang Jingying
PloS one
BACKGROUND:Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood. AIM:To assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP. METHODS:Clinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP. RESULTS:The serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05). CONCLUSIONS:The higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.
10.1371/journal.pone.0087343
Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy.
Zhang YouHua,Pan YouDong,Lin ChangDong,Zheng YaJuan,Sun Hao,Zhang HaiLong,Wang JunLei,Yuan MengYa,Duan Tao,Du QiaoLing,Chen JianFeng
Journal of molecular cell biology
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with potentially deleterious consequences for fetuses. Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Herein, we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1 (Gpbar1), with consequent upregulation of inflammatory genes in trophoblasts, leading to aberrant leukocyte infiltration and inflammation in placenta. Ursodeoxycholic acid (UDCA), a drug used clinically to treat ICP, competes with other bile acids for binding with Gpbar1 and thus inhibits bile acid-induced inflammatory response in trophoblasts and improves fetal survival in pregnant rats with obstructive cholestasis. Notably, inhibition of NF-κB by andrographolide is more effective than UDCA in benefiting placentas and fetuses. Thus, anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acid-induced inflammation and alleviating ICP-associated fetal disorders.
10.1093/jmcb/mjw025
The intervention effect of aspirin on a lipopolysaccharide-induced preeclampsia-like mouse model by inhibiting the nuclear factor-κB pathway.
Li Guanlin,Ma Liyang,Lin Li,Wang Yan-Ling,Yang Huixia
Biology of reproduction
Preeclampsia is a severe pregnancy-related disorder, and patients usually present with high circulating inflammatory factor levels and excessive activation of the nuclear factor-κB (NF-κB) pathway. Administration of aspirin (ASP) is effective for preventing preeclampsia, and thus, we propose that ASP might affect placental function by regulating the NF-κB pathway. Systemic lipopolysaccharide (LPS) (20 μg/kg) was used to induce preeclampsia-like pregnant mouse model, and low-dose ASP (15.2 mg/kg) was administrated. Here, we report significantly increased circulatory expression levels of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-6, and soluble Fms-related tyrosine kinase-1 in LPS-treated pregnant mice, accompanied by kidney and placental dysfunction. Low-dose ASP treatment significantly reversed the preeclampsia-like phenotype, lowering hypertension, decreasing proteinuria, and ameliorating fetal growth retardation. Moreover, the excessive activation of NF-κB signaling in mice placentae induced by LPS was significantly reduced by ASP. In JEG-3 cells, LPS activated the NF-κB signaling pathway by upregulating the expression of cyclooxygenase-2 (COX-2) and related inflammatory factors, whereas the invasion ability of JEG-3 cells was weakened. However, ASP administration impeded NF-κB signaling activation, downregulated COX-2 and inflammatory factor expression, and rescued trophoblast invasion. This study provides new evidence that low-dose ASP is beneficial for preeclampsia prevention by inhibiting NF-κB and its downstream signaling pathways in trophoblast cells.
10.1093/biolre/ioy025
Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity.
Muralimanoharan S,Guo C,Myatt L,Maloyan A
International journal of obesity (2005)
BACKGROUND:Maternal obesity is a major problem in obstetrics, and the placenta is involved in obesity-related complications via its roles at the maternal-fetal interface. We have recently shown a causative role for micro(mi)RNA-210, a so called 'hypoxamir' regulated by HIF-1α, in mitochondrial dysfunction in placentas from women with preeclampsia. We also reported mitochondrial dysfunction in placentas with maternal obesity. Here we hypothesized that expression of miR-210 is dysregulated in the placentas with obesity. METHODS:Placentas from uncomplicated pregnancies were collected at term from healthy weight or control (CTRL, pre-pregnancy body mass index (BMI)<25), overweight (OW, BMI=25-24.9) and obese (OB, BMI>30) women following C-section with no labor. Expression of miRNA-210 and its target genes was measured by reverse transcription-PCR and Western Blot, respectively. Mitochondrial respiration was assessed by Seahorse Analyzer in syncytiotrophoblast (ST) 72 h after cytotrophoblast isolation. RESULTS:Expression of miR-210 was significantly increased in placentas of OB and OW women with female but not male fetuses compared with CTRL placentas of females. However, expression of HIF-1α in these placentas remained unchanged. Levels of tumor-necrosis factor-alpha (TNFα) were increased in OW and OB placentas of females but not males, and in silico analysis suggested that activation of miR-210 expression in these placentas might be activated by NFκB1 (p50) signaling. Indeed, chromatin Immunoprecipitation assay showed that NFkB1 binds to placental miR-210 promoter in a fetal sex-dependent manner. Female but not male STs treated with TNFα showed overexpression of miR-210, reduction of mitochondrial target genes and decreased mitochondrial respiration. Pre-treatment of these STs with small interfering RNA to NFkB1 or antagomiR-210 prevented the TNFα-mediated inhibition of mitochondrial respiration. CONCLUSIONS:Our data suggest that the inflammatory intrauterine environment associated with maternal obesity induces an NFκB1-mediated increase in miR-210 in a fetal sex-dependent manner, leading to inhibition of mitochondrial respiration and placental dysfunction in the placentas of female fetuses.
10.1038/ijo.2015.45