ORIGINAL ARTICLE

Irisin in idiopathic foetal growth restriction

Mete Caglar • Mehmet Goksu • Bekir Sıtkı Isenlik •

Ali Yavuzcan • Musa Yılmaz • Yusuf Ustun •

Suleyman Aydin • Selahattin Kumru

Received: 20 December 2013 / Accepted: 27 March 2014

� Italian Society of Endocrinology (SIE) 2014

Abstract

Purpose The aim of the present study was to compare

maternal serum and cord blood irisin levels in females

whose pregnancies were or were not complicated by idio-

pathic foetal growth restriction.

Methods A total of 30 subjects participated. The study

group consisted of 15 female patients who were referred to

our perinatology clinic for delivery because of foetal

growth restriction developing in the third trimester. Fifteen

females with uncomplicated singleton pregnancies consti-

tuted the control group. Irisin levels were assessed in

maternal serum, as well as in serum from the umbilical

vein and artery.

Results The demographic features of the two groups were

similar (p [ 0.05). Gestational age at delivery and birth

weight were higher in females with uncomplicated preg-

nancies (p = 0.001). Umbilical artery irisin levels were

significantly lower in pregnancies complicated by foetal

growth restriction compared to controls (p = 0.003).

Umbilical artery irisin levels were positively correlated

with foetal weight (p = 0.01) and foetal abdominal cir-

cumference (measured by ultrasonography) (p = 0.01).

Maternal and umbilical vein irisin levels did not differ

between the two groups (p [ 0.05).

Conclusions The data suggest that umbilical artery irisin

levels were lower in pregnancies complicated by foetal growth

restriction. Such lower irisin levels may contribute to the

pathogenesis of this common condition, and metabolic syn-

drome may be a long-term consequence of idiopathic FGR.

Keywords Foetal growth restriction � Fat mass � Irisin �Lean mass � Metabolic syndrome � Umbilical artery

Introduction

Foetal growth restriction (FGR) is a complex problem in

modern obstetrics. The condition is characterised by sub-

optimal foetal growth which is genetically predetermined,

and affects *5–10 % of all pregnancies [1]. The term is

usually used to describe a foetus that has an estimated

weight below the 10th percentile, with reference to stan-

dard foetal weight tables [2]. FGR is associated with var-

ious perinatal complications including prematurity,

hypoxia, and academia; neonatal complications including

polycythaemia, hyperbilirubinemia, hypoglycaemia, hypo-

thermia, respiratory distress syndrome, necrotising entero-

colitis, neonatal death; and childhood complications

including neurodevelopmental delay [3, 4].

Growth restriction in utero may also compromise health in

adulthood. The Barker hypothesis suggests that endocrine-

metabolic reprogramming enabling a growth-restricted

foetus to compensate for a hostile intrauterine environment

may trigger development of metabolic syndrome in later life,

accompanied by hypertension, hypercholesterolaemia,

impaired glucose tolerance, and ischaemic heart disease

[5, 6]. Several studies have reported that FGR is associated

M. Caglar (&) � A. Yavuzcan � Y. Ustun � S. Kumru

Department of Obstetrics and Gynecology, Duzce University

School of Medicine, Duzce, Turkey

e-mail: drmete96@gmail.com

M. Goksu � B. S. Isenlik

Department of Obstetrics and Gynecology, Antalya Education

and Research Hospital, Antalya, Turkey

M. Yılmaz � S. Aydin

Department of Biochemistry and Clinical Biochemistry (Firat

Hormones Research Group) School of Medicine, Firat

University, Elazıg, Turkey

123

J Endocrinol Invest

DOI 10.1007/s40618-014-0078-5

with the development (in adulthood) of high blood pressure,

type 2 diabetes mellitus (DMT2), and reduced renal function

[7–9]. In addition, endocrinological sequelae of FGR include

short stature (of both children and adults), premature

adrenarche, and polycystic ovarian syndrome (PCOS). Early

onset growth delay and prematurity significantly increase the

risks of neurological sequelae, and motor and cognitive

delays [10].

Several studies have found significant associations

between FGR and foetal body composition (both lean and

fat masses) [11–16]. Interaction between adipose and

muscle tissues has become increasingly recognised as

playing an important role in regulation of body weight.

Both adipose and muscle tissues secrete cytokines and

other peptides, termed adipokines and myokines, respec-

tively, which mediate between tissue communication

essential to maintain metabolic homeostasis [17].

Irisin is a recently described (thus novel) hormone

secreted as a product of the ‘fibronectin type III domain-

containing 50 (FNDC5) gene of the skeletal muscle of mice

and humans [18]. More recently, irisin has been reported to

serve not only as a myokine, but also as an adipokine,

because the FNDC5 protein is secreted by white adipose

tissue [19]. FNDC5 expression is induced by the ‘peroxi-

some proliferator-activated receptor-c (PPARc) coactivator

1a0 (PGC1-a) in skeletal muscle [20]; PGC1-a plays an

important role in the exercise-induced energy expenditure

cascade. Physical activity also stimulates FNDC5 expres-

sion, in turn promoting exercise-induced browning of white

adipose tissue by increasing the expression level of

uncoupling protein (UCP 1) in white adipocytes. This

process is associated with elevated thermogenesis and a

subsequent increase in the level of energy expenditure [18,

20]. Ultimately, body weight is reduced, and metabolic

parameters including insulin sensitivity improved. There-

fore, irisin administration has been proposed as a possible

novel treatment for diabetes, obesity, and anorexia nervosa

[21, 22]. Stengel et al. showed that high irisin levels in

human plasma that were positively correlated with all of

body weight, body mass index, fat mass, cell body mass,

fat-free mass, and water content. Irisin levels were also

positively correlated with the concentrations of circulating

insulin, whereas no correlations were observed when irisin

levels were compared to those of thyroid-stimulating hor-

mone and cortisol. These findings suggest that irisin acts

independently of the hypothalamus–pituitary–adrenal

gland axis [20]. In addition, bariatric surgery-induced

weight loss has been reported to be associated with a

decrease in irisin levels, independent of BMI [23]. Several

studies have reported lower irisin levels in patients with

DMT2; irisin was thus suggested to play an important role

in glucose intolerance [24, 25]. Bostrom et al. showed that

even relatively short-term irisin therapy improved glucose

haemostasis, and triggered weight loss, in obese mice. It

remains unclear whether long-term therapy and/or higher

doses of irisin would be associated with continued or

maintained weight loss [18]. Fernandez-Real et al. sug-

gested that reduced production of irisin in the muscle/adi-

pose tissues of obese patients and those with DMT2 might

explain the lower levels of brown or beige adipocytes in the

adipose tissue of such patients [17]. Further, irisin has been

suggested to determine insulin sensitivity in humans [26].

Chronic kidney disease (CKD) is a further condition

characterised by alterations in energy expenditure, a high

prevalence of metabolic imbalance, and abnormal energy

homeostasis. CKD patients have lower resting irisin levels

independent of their concentrations of high-density lipo-

protein. The mechanism underlying the decrease in irisin

levels in CKD patients remains unknown. However,

indoxyl sulphate, a protein-bound uraemic toxin, may

downregulate FNDC5 expression in skeletal muscle cells

and reduce irisin levels in cultured cells [27].

Together, these data suggest that irisin plays an impor-

tant role in human metabolism. Long-term monitoring of

children and adults who experienced FGR in utero suggests

that FGR can be regarded as a form of metabolic syndrome

encountered during intrauterine life. Thus, the aim of the

present study was to measure irisin levels in maternal

serum, and arterial and venous cord blood, in pregnancies

complicated by idiopathic FGR.

Materials and methods

The present study was approved by the Ethics Committee

and Institutional Review Board of Antalya Education and

Research Hospital, where the study was conducted. The

parents of all study patients provided written informed

consent. A total of 30 subjects were included. All underwent

caesarean section under general anaesthesia; females who

entered the active phase of labour were excluded because

labour may affect irisin levels. The study group consisted of

15 females who were referred to our perinatology clinic

because FGR developed in the third trimester. A diagnosis

of idiopathic FGR during the third trimester, thus FGR with

no apparent cause, was the inclusion criterion. The exclusion

criteria were as follows: active labour; multiple gestation;

maternal medical conditions including pre-gestational dia-

betes mellitus, renal insufficiency, an autoimmune disease

(e.g. systemic lupus erythematosus), cyanotic cardiac dis-

ease, any pregnancy-related hypertensive disease (e.g.

chronic hypertension, gestational hypertension, or pre-

eclampsia), or anti-phospholipid antibody syndrome;

maternal substance use or abuse (e.g. consumption of

tobacco, alcohol, cocaine, or narcotics); any infectious dis-

ease (e.g. malaria, cytomegalovirus, rubella, toxoplasmosis,

J Endocrinol Invest

123

or syphilis); any genetic or structural disorder (e.g. trisomy

13, trisomy 18, congenital heart disease, or gastroschisis);

any exposure to a teratogen (e.g. cyclophosphamide, val-

proic acid, or an antithrombotic drug); any placental disor-

der; and any umbilical cord abnormality [28]. The control

group was composed of 15 females with uncomplicated

singleton pregnancies. All foetuses in the control group

showed normal intrauterine foetal growth (appropriate for

gestational age; AGA) as confirmed by routine ultrasonog-

raphy. All subjects were similar in terms of ethnic and

socioeconomic characteristics.

Estimated foetal weight was calculated from ultrasono-

graphic measurements of head circumference, abdominal

circumference, and femur length. Gestational age was

calculated by reference to the date of the last menstrual

period and was confirmed by routine ultrasonography at

11–12 weeks of gestation. FGR was considered present

when a foetus weighed below the 10th percentile for ges-

tational age, with reference to a standard growth curve. A

foetus was defined as having a weight AGA when the

weight lay between the 10th and 90th percentiles on the

same standard growth curve. All ultrasonographic evalua-

tions were performed using a Logic5 Pro 3.5-MHz convex

transducer (GE Medical Systems, Milwaukee, WI); a single

sonographer collected all data.

Maternal venous blood samples were drawn after 8 h of

fasting from the antecubital vein into flat biochemical tubes

using a vacutainer system. Blood was drawn immediately

before the induction of anaesthesia that preceded delivery.

Immediately after delivery, a 10- to 15-cm-long segment of

the umbilical cord was double clamped to obtain a foetal

blood sample. Aprotinin was added (to 500 kallikrin units/

mL) to prevent proteolysis of irisin. Samples were centri-

fuged at 3,0009g for 5 min at room temperature, and the sera

stored at -80 �C prior to analysis. Irisin levels were mea-

sured using a human irisin ELISA assay kit (Cat No: EK-

067-52; Phoenix Pharmaceuticals, Burlingame, CA). The

minimum detectable concentration of irisin was 9 ng/mL

and the intra- and inter-assay coefficients of variation,\4–6

and\8–10 %, respectively. Samples were batch-assayed to

minimise inter-assay variability. All measurements were

performed following the manufacturer’s recommendations

and absorptions were read on an ELx 800 Microplate Reader

(BioTek Instruments Inc., Winooski, VT).

Statistical analysis

The PASW statistical package (version 18) was used for

statistical analyses. Data distribution was assessed with the

aid of the Shapiro–Wilk test. Means and standard devia-

tions were calculated when data were normally distributed,

and medians for data that showed non-parametric distri-

butions. Categorical variables are expressed as frequencies

with percentages. Continuous variables were compared

using the independent samples t test or the Mann–Whitney

U test, as appropriate. Correlations between irisin levels, on

the one hand, and demographic and baseline patient and

foetal characteristics, on the other, were evaluated by cal-

culation of Spearman’s rho values. A p value \0.05 was

considered to reflect statistical significance.

Results

The demographic and baseline characteristics of the two

groups are shown in Table 1. All of maternal age, body mass

index (BMI), gravidity, and parity, were similar between the

two groups (all p values[0.05). Correlations between irisin

levels, and demographic and baseline characteristics of

patients and foetuses, were sought. A significant positive

correlation was evident between umbilical artery irisin levels

and all of birth weight (p = 0.01, r = 0.462), foetal

abdominal circumference as measured ultrasonographically

(p = 0.01, r = 0.457), birth height (p = 0.016, r = 0.434),

and gestational age at delivery (p = 0.046, r = 0.462).

Umbilical artery irisin levels did not correlate with either

maternal age (p = 0.231, r = -0.225) or BMI (p = 0.66,

r = -0.084). Moreover, irisin levels in maternal sera and

the umbilical vein did not correlate with any parameter

examined (all p values [0.05).

The irisin levels are shown in Table 2. There was no

significant difference in maternal irisin level between the

Table 1 Characteristics of the

study population

BMI body mass index, AC

abdominal circumference

* p value\0.05 was considered

statistically significanta Mean ± SDb Median (min–max)

Control group (n = 15) Study group (n = 15) p value

Agea 28.5 ± 6.5 27.9 ± 5 0.781

BMI (kg/m2)a 29.3 ± 3.3 26.8 ± 4.3 0.099

Gestational age (days)a 275.2 ± 5.8 263.8 ± 10.03 0.001*

Gravidityb 2 (1–7) 2 (1–5) 0.412

Parityb 1 (0–4) 1 (0–4) 0.461

Newborn weight (kg)a 3,521.3 ± 325.6 2,248 ± 265.7 \0.001*

Newborn height (cm)a 50.3 ± 0.7 47.3 ± 1.7 \0.001*

Foetal AC (cm)a 38.6 ± 1.7 32.4 ± 1.5 \0.000*

J Endocrinol Invest

123

test and control groups (1,695.4 vs. 1,171.1 ng/mL,

p = 0.806). The umbilical vein irisin levels were also

similar in the two groups (370.2 vs. 279 ng/mL,

p = 0.486). However, umbilical artery irisin levels were

significantly higher in the control compared to the test

group (361.3 vs. 252.8 ng/mL, p = 0.003). Irisin levels in

the umbilical artery, umbilical vein, and maternal serum

were not influenced unaffected by foetal gender (Table 3).

Irisin levels did not vary significantly between subjects of

normal BMI and overweight-obese subjects (Table 4).

Discussion

FGR is an important cause of perinatal morbidity and

mortality. Doppler velocimetry of the umbilical artery is

recommended as the primary surveillance tool to monitor

pregnancies in which FGR is suspected [29]. The umbilical

artery transfers deoxygenated blood and waste from the

foetus to the placenta. Therefore, umbilical artery param-

eters are the measures of foetal well-being and metabolic

state.

In the present study, maternal and umbilical vein irisin

levels did not differ significantly between control and test

patients; but umbilical artery irisin levels were significantly

lower in the test group. This finding has two implications.

First, foetuses with FGR are at higher risk of developing

obesity, hypertension, hypercholesterolaemia, cardiovas-

cular disorders, glucose intolerance, and type 2 DM at later

ages, compared to the general population [30]. Hales and

Barker proposed that the observed epidemiological asso-

ciation between poor foetal and infant growth, and the

subsequent development of type 2 DM and metabolic

syndrome, are caused by poor nutrition early in life, which

triggers permanent changes in glucose–insulin metabolism.

The ‘‘thrifty phenotype’’ hypothesis suggests that insulin

secretion increases and insulin resistance decreases in such

foetuses, in an effort to adapt to unfavourable conditions in

utero. At later ages, metabolic syndrome can arise when

obesity develops, associated with inadequate physical

activity [31]. These long-term consequences of FGR are

thought to be caused by endocrine-metabolic foetal adap-

tations, in an effort to adjust to unfavourable intrauterine

conditions [31]. Several studies have reported lower irisin

levels in patients with type 2 DM [17, 24, 25]. Fernandez-

Real et al. suggested that all of obesity, metabolic syn-

drome, type 2 DM, and anorexia nervosa, could be treated

by (artificially) increasing irisin levels [17, 21, 22]. Con-

sistent with the above-mentioned ‘‘thrifty phenotype’’

hypothesis, the hypothesis of Barker, and the findings of

several studies, we found that umbilical artery irisin levels

were lower in foetuses with FGR compared to those of the

control group. This may either indicate that FGR is in play,

or may be the cause of FGR. The decrease in umbilical

artery irisin levels during intrauterine period may be a key

element of the observed association between FGR and

development of metabolic syndrome in the long term.

Further, analysis of irisin levels may aid the diagnosis and

treatment of metabolic syndrome. Second, it is known that

infants with FGR differ in body composition in comparison

to normal infants, exhibiting reductions in the levels of

both fat and lean mass (bone and muscle) [11]. Bernstein

et al. [12] found that foetal fat and lean body masses had

unique growth profiles and that measurement of foetal fat

Table 2 Irisin levels in control

and study groups

* p value\0.05 was considered

statistically significanta Median (min–max)

Control group (n = 15) Study group (n = 15) p value

Irisin umbilical arterya 361.3 (221.2–889.8) 252.8 (157.9–351.7) 0.003*

Irisin umbilical veina 370.2 (115.3–1,316.7) 279 (130–5,573.4) 0.486

Irisin maternala 1,695.4 (562.4–25,981) 1,171.1 (391.7–5,527.9) 0.806

Table 3 Irisin levels and

newborn gender

a Median (min–max)

Boy (n = 19) Girl (n = 11) p value

Irisin umbilical arterya 289.1 (176.5–889.8) 351.7 (157.9–758.2) 0.735

Irisin umbilical veina 253.9 (130.0–5,573.4) 370.2 (115.3–1,316.7) 0.420

Irisin maternala 1,362.8 (470.9–25,981) 1,026.9 (391.7–3,977.9) 0.445

Table 4 Irisin levels and

maternal BMI

a Median (min–max)

BMI \25 (n = 7) BMI C25 (n = 23) p value

Irisin umbilical arterya 302.4 (252.8–351.7) 245.7 (157.9–889.8) 0.598

Irisin umbilical veina 236.1 (130.0–386.9) 370.2 (115.3–5,573.4) 0.077

Irisin maternala 1,070.1 (562.4–4,376.4) 1,362.8 (391.7–25,981) 0.737

J Endocrinol Invest

123

level was an optimally sensitive and specific marker of

abnormal foetal growth, because fat mass exhibited an

accelerated growth rate during late gestation. Lapillonne

et al. [13] reported that total body fat, lean mass, and bone

mineral content in small-for-gestational-age infants were

all significantly less than those of AGA infants. Gardeil

et al. [14] considered that measurement of foetal fat level in

the abdominal wall was a simple and sensitive technique

that accurately predicted low birth weight, and might also

predict the development of FGR.

Stengel et al. [20] analysed irisin levels in adults

exhibiting a broad spectrum of body weights. The results

indicated that circulating irisin levels were influenced by

BMI; the highest levels were noted in severely obese

patients. Human data on exercise-dependent irisin pro-

duction by muscles, and secretion thereof into the circu-

lation, are inconsistent. However, the observed association

between plasma irisin levels and BMI is robust [22]. In the

present study, we did not note any significant difference

between irisin levels of subjects of normal BMI and

overweight-obese subjects.

We measured maternal and umbilical cord irisin levels

because differences in foetal body composition are

observed between normal neonates and those affected by

idiopathic FGR. We found that umbilical artery irisin

levels were lower in FGR foetuses, consistent with the data

of several previous studies [20, 22, 25]. As both fat and

lean masses are lower in foetuses affected by idiopathic

FGR, it is not surprising that umbilical artery irisin levels

were lower (than the control value) in such newborns. In

addition, umbilical artery irisin levels correlated positively

with birth weight and height, and ultrasonographic foetal

abdominal circumference. However, umbilical vein and

maternal irisin levels were similar whether or not preg-

nancies were complicated by idiopathic FGR. Although we

found a significant correlation between umbilical artery

irisin level and the gestational age, Ebert et al. [32] found

no difference between the irisin level during pregnancy and

after delivery. In the present study, it may be appropriate to

ignore any apparent correlation with gestational age

because the two groups were unmatched for this parameter,

and this may have been reflected in differences in man-

agement of the two groups [28]. Although the prospective

nature of the present study is an advantage, our sample size

was small.

To our knowledge, this is the first study to investigate

possible relationships between irisin levels in maternal and

umbilical cord blood in pregnancies affected by idiopathic

FGR, and the development of FGR per se. In conclusion,

our data suggest that lower umbilical artery irisin levels in

pregnancies with idiopathic FGR may contribute to the

pathogenesis of this common disease, and metabolic syn-

drome in the long term. The utility of maternal and cord

blood irisin levels as markers of FGR remains controver-

sial, and larger scale studies are warranted to clarify this

point and confirm our current results.

Conflict of interest The authors declare that they have no conflict

of interest.

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