Chemerin is present in human cord blood and is positively correlated with birthweight




Objective


Chemerin, a novel adipokine, has been implicated in adipogenesis, inflammation, and metabolism. The aims of this study were to determine the presence of chemerin in cord blood and its association with birthweight.


Study Design


This cross-sectional study included the following: (1) twins with (n = 24) or without (n = 28) birthweight discordancy; and (2) singletons subclassified into small-for-gestational-age (SGA; n = 18); appropriate for gestational age (AGA; n = 33); and large-for-gestational-age (LGA; n = 8). Cord blood chemerin was determined. Parametric and nonparametric statistics were used for analysis.


Results


The results of the study included the following: (1) within the discordant twins group, the median chemerin concentration was significantly lower in the SGA group than in their cotwins; (2) within singletons, the median chemerin concentration was significantly higher in the LGA than the AGA newborns; and (3) the regression model revealed that chemerin was independently associated with birthweight.


Conclusion


Cord blood chemerin is present in cord blood and its concentrations are positively correlated with birthweight. These novel findings support a role of adipokines in fetal growth.


Fetal growth is determined by a complex interaction between environmental, genetic, and hormonal factors. The implicit paradigm that has governed many studies concerning fetal growth is that the fetal insulin–insulin growth factor system is the most important among the hormonal factors. Although there is ample empirical and epidemiological evidence to support this view, independent studies have recently revealed an association between adipokines and fetal growth and development.


Adipose tissue has emerged as a powerful and potent endocrine organ that can exert a systemic effect via the production of adipokines. Several adipokines play an important role in the regulation of insulin sensitivity, lipid metabolism, and energy homeostasis as well as inflammation. The physiological importance of adipokines in adults has led to the hypothesis that alterations in circulating maternal concentrations of adipokines are associated with normal gestation as well as in complications of pregnancy including preeclampsia, gestational diabetes mellitus, preterm birth, delivery of large-for-gestational-age (LGA) newborns, small-for-gestational-age (SGA) neonates, and others.


Similarly, circulating fetal adipokines have been implicated in the development of human fetus. The following findings suggest an association between adipokines and fetal growth: (1) several adipokines have been detected in cord blood including leptin, adiponectin, visfatin, resistin, omentin-1, vaspin, apelin, retinol-binding protein 4 (RBP4), and others ; (2) circulating fetal concentrations of some adipokines are higher than in their mothers, suggesting fetal production of these active molecules; (3) a positive correlation has been reported between cord blood adiponectin, leptin, visfatin, resistin, RBP4, and birth weight; (4) human placenta expresses leptin , resistin, visfatin and other adipokines; and (5) receptors of adiponectin, leptin , and retinol-binding protein transcripts were localized in trophoblast cells. Taken together, these data suggest that adipokines play a role in fetal growth.


Chemerin, a novel adipokine, was originally identified as a retinoid-responsive gene in psoriatic skin lesions. Chemerin is a natural ligand of chemerin receptor (CMKLR1) and serves as a ligand for additional receptors. Chemerin has been suggested to play a regulatory role in both inflammation and metabolism.


The evidence supporting a role for this protein in energy homeostasis includes the following: (1) white adipose tissue expresses high levels of chemerin and its receptor ; (2) maturation of 3T3-L1 cells into adipocytes is associated with increased expression and secretion of bioactive chemerin ; (3) knockdown of chemerin or its receptor in adipocyte culture resulted in reduced perilipin, glucose transporter 4, adiponectin, and leptin expression ; (4) adipose tissue explants from obese patients secretes more chemerin than lean subjects, and chemerin messenger ribonucleic acid (mRNA) expression is significantly higher in adipose tissue of patients with type 2 diabetes mellitus; and (5) studies in humans have found an association between chemerin and components of metabolic syndrome, diabetes, and alterations in body mass index (BMI). This unique set of properties in addition to a mounting body of evidence regarding the role of adipokines in fetal growth prompted us to investigate the association between cord blood adiponectin and birthweight.


To the best of our knowledge, the association between cord blood chemerin and birthweight has not been reported. Moreover, only a handful of studies have determined its concentrations in pregnant women. Pfau et al reported that circulating chemerin in pregnant women with and without gestational diabetes were positively correlated with homeostasis model assessment of insulin resistance. Consistent with the aforementioned report, Stepan et al found higher chemerin concentrations in patients with preeclampsia than in normal controls.


In addition, these authors reported a positive correlation between chemerin and blood pressure, free fatty acids, cholesterol, triglycerides, leptin, adiponectin, and C-reactive protein. Subsequently, Duan et al have corroborated the association between high maternal serum concentrations and preeclampsia.


Thus, the aims of this study were to determine the presence of chemerin in cord blood and to evaluate its association with birthweight (specifically, birthweight categories) in singletons and twins with and without growth restriction.


Materials and Methods


Subjects


This cross-sectional study included 2 groups: (1) twins (n = 52) and (2) singletons (n = 59). The twins group included 26 pairs of dichorionic twins, which were further divided according to the presence (n = 12) or absence (n = 14) of birthweight discordancy.


The inclusion criteria for the discordant twins group were as follows: (1) dichorionic twins gestation with discordant growth according to the estimated fetal weight by an ultrasound scan; (2) the estimated fetal weight of the smaller twin was below the 10th percentile, and the birthweight percentile below the 10th percentile was confirmed at birth; (3) the estimated fetal weight of the larger cotwin was between the 10th and the 90th percentiles, and the birthweight percentile between the 10th and the 90th percentiles was confirmed at birth; and (4) the absence of the end diastolic flow or reverse flow in the umbilical artery in Doppler studies of the smaller twin.


The inclusion criteria for the concordant twins group were dichorionic twin gestation with concordance growth according to the estimated fetal weight by an ultrasound scan and the estimated fetal weight of both twins was between the 10th and 90th percentiles. The birthweight percentile between the 10th and 90th percentiles was confirmed at birth.


The inclusion criteria for the singletons group were a normal pregnancy; a single gestation; and a gestational age 42 weeks or less of gestation. Newborns in the singleton group were further divided by birthweight percentile into the following 3 groups: (1) SGA, defined as a birthweight percentile in the 10th percentile or less (n = 18); (2) appropriate for gestational age (AGA) defined as a birthweight between the 10th and 90th percentile (n = 33); and (3) LGA defined as a birthweight above the 90th percentile and greater than 4000 g (n = 8). Birthweight percentiles were calculated according to population-based birthweight standards.


Exclusion criteria for both twins and singletons neonates included the following: (1) prior abnormal maternal metabolic or medical conditions; (2) pregnancies complicated with congenital anomalies or chromosomal abnormalities; (3) abnormal 50 g glucose challenge test, performed between 24 and 28 weeks of gestation ; (4) preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome or the fetal demise of 1 twin; (5) preterm prelabor rupture of membranes; and (6) clinical signs or symptoms of chorioamnionitis.


Definitions


Gestational age at delivery was determined by ultrasound examination during the first trimester. Chorionicity was established by ultrasound examination in the first trimester in which 2 separated gestational sacs were documented and confirmed after birth by a different sex or by placental histology. Growth discordance was defined as the difference of 25% or less in birthweight expressed as a proportion of the birthweight of the larger twin. Oligohydramnious was defined as a single vertical pocket of less than 2 cm.


Upon enrollment, pulsed-wave and color Doppler ultrasound examination of the umbilical arteries was performed with a real-time scanner equipped with a 3.5 MHz or a 5 MHz curvilinear probe. Umbilical artery Doppler velocimetry was defined as abnormal in the presence of abnormal waveforms (absent or reversed end-diastolic velocities). Maternal BMI was calculated upon enrollment according to the following formula: weight (kilograms)/ height (meters) 2 .


Birthweight was obtained immediately after the delivery using a standard electrical scale. Recumbent length was measured on the second day of life with an infantometer containing a stationary headboard, a movable footboard, and a built-in centimeter scale.


Methods


Arterial cord blood was obtained from the newborns at the time of delivery and before the separation of the placenta, and chemerin concentration was determined in all newborns. Serum obtained by centrifugation of blood was immediately frozen and stored at –70°C until further analysis. Chemerin concentration was determined using an enzyme-linked immunosorbent assay kit (Mediagnost, Tubingen, Germany). The sensitivity of the chemerin assay was 5 pg/mL. Inter- and intraassay coefficients of variability were below 6%.


The protocol was approved by the institutional review board at the Sheba Medical Center, and all patients provided a written informed consent.


Statistical analysis


Normality of the data was tested using the Shapiro-Wilk or Kolmogorov-Smirnov tests. Data are presented as median and interquartile range (IQR). Comparison between 2 paired samples was conducted with a paired Student t test or a Wilcoxon signed ranks test, and comparison between unrelated variables was conducted with a Student t test or a Mann-Whitney U test, as appropriate. Comparison between more than 2 groups was conducted by 1 way analysis of variance or a Kruskal Wallis test. Correlation between variables was assessed in a pooled analysis of all the neonates using either a Pearson or a Spearman’s rank correlation as appropriate.


Linear regression analysis was used to determine which factors were significantly and independently correlated with cord blood chemerin variations. The following parameters were included in the model: maternal age, maternal BMI, gestational age at blood collection, and birthweight. Significance was accepted at P < .05. Statistical analyses were conducted using the IBM Statistical Package for the Social Sciences (IBM SPSS version 19; IBM Corp Inc, Armonk, NY).


Results


Table 1 displays the demographic and clinical characteristics of the twins study population. Of the 26 enrolled pregnant women, 12 had severe growth-discordant twins (median birthweight discordancy: 32.5%; IQR, 26.7–40.9%); in all cases the smaller twin was SGA (median: third percentile; IQR, third to fifth percentile), and the cotwin was AGA (median: 37.5th percentile; IQR, 25th to 50th percentile) ( Table 1 ). Among the 12 SGA neonates, 10 had oligohydramnious. The control group included 14 pairs of concordant twins (median birthweight discordancy: 6.9%; IQR, 3.4–10.7%), and both twins were AGA ( Table 1 ).



TABLE 1

Demographic and clinical characteristics of twins





































































Demographic Discordant twins (n = 24) Concordant twins (n = 28) P value
Gestational age at delivery, wks 37.0 (34.5–38.0) 37.0 (35.0–38.0) .86
Maternal age, y 31.5 (28.0–33.7) 29.0 (24.0–33.2) .30
Maternal BMI, kg/m 2 28.1 (26.6–28.1) 28.7 (27.2–30.5) .98
Gravidity 2.5 (1.0–4.7) 2.5 (1–3.2) .77
Parity 1 (1.0–3.7) 2 (1–3) .62
Larger twin birthweight, g 2642 (2266–2881) 2492 (2066–2800) .31
Smaller twin birthweight, g 1780 (1483–2086) 2265 (1996–2561) .01
Larger twin birth length, cm 47 (45.2–48.7) 47.0 (43.4–48.6) .98
Smaller twin birth length, cm 41.7 (38.6–44.5) 46.0 (43.2–48.0) .02
Larger twin percentile 37.5 (25–50) 25 (20–47.5) .10
Smaller twin percentile 3 (3–5) 15 (15–30) .001
Discordancy, % 32.2 (26.7–40.9) 6.9 (3.4–10.7) .001

Data are presented as median and interquartile range.

BMI, body mass index.

Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.


Cord blood chemerin within the discordant twins group


Within the discordant twins pairs, median cord blood chemerin concentration was significantly lower in SGA newborns than in their AGA cotwin (median: 78.9 ng/mL; IQR, 56.4–83.0 ng/mL vs median: 106.8 ng/mL; IQR, 83.5–133.3 ng/mL; P = .01; Figure 1 ).




FIGURE 1


Comparison between cord blood chemerin concentrations in dichorionic twin gestations with and without growth discordance

In twins, median chemerin cord blood concentration was significantly lower in SGA than in AGA neonates in the presence of discordant growth. There was no significant difference in median chemerin cord blood concentration between the larger (heavier) neonates and smaller (lighter) neonates in pregnancy without growth discordance.

AGA, appropriate for gestational age; SGA, small-for-gestational-age.

Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.


Cord blood chemerin within the concordant group


Within the concordant twins group, there were no significant differences in median cord blood chemerin concentrations between the AGA neonates (smaller AGA, 112.8 ng/mL; IQR, 80.9–125.3 ng/mL vs larger AGA, 104.5 ng/mL; IQR, 89.2–134.3 ng/mL; P = .9; Figure 1 ).


Correlations


Bivariate analysis in the 52 twin newborns revealed significant positive correlation between cord blood chemerin and birthweight (r = 0.36, P = .008) and birth length (r = 0.31, P = .02).


Cord blood chemerin in SGA, AGA, and LGA singleton newborns


Table 2 displays the demographic and clinical characteristics of the singleton study population. Median chemerin cord blood concentrations were significantly higher in the LGA than in the AGA neonates (LGA, 149.4 ng/mL; IQR, 125.3–169.8 ng/mL vs AGA, 119.9 ng/mL; IQR, 95.5–135.7 ng/mL; P = .04; Figure 2 ). The median chemerin cord blood concentrations were comparable between SGA (133.8 ng/mL; IQR, 110.9–162.8 ng/mL) and both LGA ( P = .5) and AGA neonates ( P = .1, Figure 2 ).



TABLE 2

Demographic and clinical characteristics of singletons




















































Demographic SGA (n = 18) AGA (n = 33) LGA (n = 8) P value
Gestational age at delivery, wks 39.0 (38.0–40.0) 39.3 (37.4–40.1) 40.0 (39.2–41.7) .06
Maternal age, y 29.0 (26.0–33.0) 32.0 (28.0–35.2) 32.0 (27.7–35.0) .30
Maternal BMI, kg/m 2 24.7 (23.0–29.0) 27.5 (24.7–28.8) 25.8 (24.8–28.1) .18
Gravidity 3 (1–4) 2 (1–3) 3.5 (2–5.5) .17
Parity 2 (1–3) 2 (1–3) 2 (2–4.5) .32
Birthweight, g 2425 (2250–2630) 3115 (2913–3442) 4235 (4133–4291) .001
Percentile 5 (3–5) 35 (25–55) 95 (90–97) .001

Data are presented as median and interquartile range.

AGA, appropriate for gestational age; BMI, body mass index; LGA, of large-for-gestational-age; SGA, small-for-gestational-age.

Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.



FIGURE 2


Comparison between cord blood chemerin concentrations in SGA, AGA, and LGA neonates

Median chemerin cord blood concentration was significantly higher in LGA than in AGA neonates. There were no significant differences in the median chemerin cord blood concentration between SGA and either LGA or AGA neonates.

AGA, appropriate for gestational age; BMI, body mass index; LGA, of large-for-gestational-age; SGA, small-for-gestational-age.

Mazaki-Tovi. Cord blood chemerin is associated with birthweight. Am J Obstet Gynecol 2012.


The association between cord blood chemerin concentration and possible confounding factors was further studied by regression analysis in a pooled data of all participants in the study. Gestational age at delivery ( P < .001) and birthweight ( P = .005) were independently associated with cord blood chemerin concentrations after adjustment for maternal age and maternal BMI.


Comment


The present study provides evidence, for the first time, that chemerin is present in the cord blood. Moreover, we were able to report that higher concentrations of cord blood chemerin were detected in AGA compared with SGA cotwins as well as in LGA compared with AGA singletons.


The source(s) of chemerin in cord blood is currently unknown; however, several potential sources can be hypothesized, including placenta, the maternal compartment, and fetal tissues. Goralski et al have reported that chemerin mRNA is expressed in human placenta, supporting the possibility that the placenta is a source of fetal chemerin. This finding was subsequently corroborated in a recent study by Garces et al in which, using immunohistochemistry, chemerin was localized to the cytotrophoblast and Hofbauer’s cells in term human placenta. Additional information is needed to determine whether chemerin is secreted by the placenta and what is the relative contribution of the placenta to fetal circulation.


An additional putative source of circulating fetal chemerin is the maternal compartment. Detection of chemerin in maternal circulation has been reported by Pfau et al, Stepan et al, and Duan et al. Importantly, chemerin is translated as a 163 amino acid preproprotein, secreted as an 18 kDa inactive proprotein and undergoes extracellular serine protease cleavage of the C-terminal portion of the protein to generate the 16 kDa active chemerin. The relatively high molecular weight of this protein suggests that simple transport of chemerin across the placenta is not plausible. Thus far, specific placental transport for chemerin has not been identified. In conclusion, although conceivable, it is unlikely that either the placental or the maternal compartments are a major source of fetal circulating chemerin.


High concentrations in LGA newborns as well as positive correlation between cord blood chemerin and birthweight point to fetal tissues as the main source of fetal circulating chemerin. There is a paucity of scientific data regarding expression and secretion of chemerin by fetal tissues. In adults, expression of chemerin has been identified in various tissues including pancreas, lung, pituitary, and ovary; however, the most abundant expression is in adipose tissue and liver. Indeed, the term hepatoadipokine has been coined by the group including Stumvoll and Blüher to describe this protein.


The liver is one of the largest organs in term newborns, and neonatal fat mass constitutes up to 14% of total birthweight. Fetal contribution to cord blood chemerin is further supported by the finding that along with the liver and white adipose tissue, the highest levels of chemerin expression have been detected in brown adipose tissue, which is abundant in human term neonates. Thus, it is conceivable that these organs are responsible for the presence of chemerin in fetal circulation. Noteworthy is the finding that epithelial cells in the fetal intestine produce chemerin, suggesting that in fetal life additional tissues are capable of producing this protein.


In contrast to twin gestation, we did not find a significant difference in cord blood chemerin between SGA and AGA singleton newborns. The discrepancy of these findings is unclear but may be related to differences in the clinical characteristic between the 2 groups. Singleton SGA newborns were included in the study strictly on the ground of birthweight percentile, whereas the SGA included in the twin group also had abnormal blood flow in the umbilical artery, and most of them had oligohydramnios. In addition, the median birthweight percentile for the twin SGA group was lower compared with the SGA singletons.


Finally, comparison between SGA and AGA singleton gestation does not allow us to completely eliminate maternal known and unknown confounding factors that may affect chemerin concentration. Such a confounding factor may be a maternal proinflammatory state previously reported in mothers of SGA neonates. Clearly this limitation does not exist in twin gestation. Hence, twin gestation can be considered a more reliable model for evaluating differences in cord blood chemerin concentration.


An additional novel finding in this study is the positive association between cord blood chemerin and birthweight. Higher chemerin concentrations in AGA versus SGA cotwins, as well as in LGA versus AGA singletons, are consistent with this finding. A plausible explanation for the positive correlation between cord blood chemerin and birthweight is the production by the liver and adipose tissue. Of note, both liver size and fat deposit are positively correlated with birthweight. The latter may be especially pertinent in this context because although neonatal fat mass constitutes up to 14% of total birthweight, it explains almost half of its variance. Moreover, chemerin has been implicated in adipogenesis and adipose tissue obtained from obese patients secretes more chemerin than those taken from lean adults. Collectively these data suggest that the production of chemerin by fetal liver and especially by adipose tissue may explain the association between birthweight and cord blood concentrations of this adipokine.


Interestingly, a recent study by the group including Goralski demonstrated that the chemerin receptor (CMKLR1) deficiency in mice is associated with reduced embryonic musculature and a lower embryo mass compared with wild-type controls. Indeed, the wet weight of the CMKLR1 +/– and CMKLR1 –/– embryos was approximately 10% lower at mid- and late gestation compared with wild-type controls. Furthermore, embryo mass appeared to persist into adulthood, resulting in a lower total body mass and bone-free lean body mass at adulthood in CMKLR1-deficient mice. Collectively these finding suggest that a putative mechanism by which chemerin is associated with birthweight involves reduced activation of CMKLR1 and consequently diminished skeletal muscle mass.


Several strengths and limitations of our study should be acknowledged. The cross-sectional design of the present study precludes comment on causality in the association between cord blood chemerin and fetal growth. The elucidation of molecular or cellular mechanisms to account for the association between chemerin and fetal growth was beyond the scope of this work.


An additional limitation is the relatively small number of neonates in the LGA groups. Nevertheless, despite the modest sample size, we were able to report a statistically significant difference between LGA and AGA newborns. Furthermore, inclusion criteria for this group included both birthweight above the 90th percentile and absolute weight of more than 4000 g, suggesting that neonates included in this group genuinely represent aberrant fetal growth. Among the strengths of our study is the use of the discordant and concordant twin gestation; comparison between SGA, AGA, and LGA newborns; well-defined inclusion criteria for the study group; and meticulous statistical methods.


In conclusion, several features about chemerin suggest that this molecule might be important for understanding fetal growth. The biological importance of this protein resides in the fact that it is a mediator of adipogenesis, myogenesis, and energy balance. Our study provides the first observation that chemerin is present in human cord blood and is correlated with birthweight. The results of this study lend support to the concept that adipokines, and particularly chemerin, may play a role in the complex and intriguing process of fetal growth. Further exploration of the mechanism(s) governing the production and secretion of chemerin and the biological function of this protein in fetal life is merited.


This study was supported by grants from the Mintz-Law Foundation of Tel-Aviv University and the Talpiot Medical Leadership Program , Sheba Medical Center, Tel Hashmer, Israel (all to S.M.-T.).


The authors report no conflict of interest.


The first 2 authors contributed equally to the study and article.


Cite this article as: Mazaki-Tovi S, Kasher-Meron M, Hemi R, et al. Chemerin is present in human cord blood and is positively correlated with birthweight. Am J Obstet Gynecol 2012;207:412.e1-10.



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May 15, 2017 | Posted by in GYNECOLOGY | Comments Off on Chemerin is present in human cord blood and is positively correlated with birthweight

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