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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1553
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 2397-2402
Copyright © 2005 by The Endocrine Society

Adiponectin Expression in Human Fetal Tissues during Mid- and Late Gestation

S. Corbetta, G. Bulfamante, D. Cortelazzi, V. Barresi, I. Cetin, G. Mantovani, S. Bondioni, P. Beck-Peccoz and A. Spada

Institute of Endocrine Sciences, Fondazione IRCCS Ospedale Maggiore Policlinico (S.C., D.C., G.M., S.B., P.B.-P., A.S.), Unit of Pathology (G.B., V.B.) and Obstetrics and Gynecology (I.C.), Department of Medicine Surgery and Dentistry, San Paolo Hospital Medical School, University of Milan, 20122 Milan, Italy

Address all correspondence and requests for reprints to: Sabrina Corbetta, M.D., Institute of Endocrine Sciences, Ospedale Maggiore IRCCS, Via F. Sforza, 35, 20122 Milan, Italy. E-mail: sabrina.corbetta{at}unimi.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Adiponectin (ApN), an adipocytokine expressed in adipocytes with antidiabetic and antiatherogenic actions, has been detected in cord blood, suggesting a putative role in intrauterine fetal development. The aim of this study was to confirm the presence of ApN in the fetal circulation and directly investigate ApN expression in fetal tissues. The study showed high ApN levels in umbilical venous blood from fetuses [n = 44; 31.2 ± 14.1 (SD) mg/liter in umbilical vs. 8.4 ± 4.0 in maternal circulation (P < 0.0001)] that positively correlated with gestational age. By using RT-PCR, Western blotting, and immunohistochemistry, ApN was detected in several fetal tissues at mid- and late gestation (from 14 to 36 wk) but not in the placenta. ApN was expressed in tissues of mesodermic origin, i.e. brown and white adipocytes, skeletal muscle fibers of diaphragm and iliopsoas, smooth muscle cells of small intestine and arterial walls, perineurium and renal capsule, and tissues of ectodermal origin, i.e. epidermis and ocular lens. The distribution of ApN expression in nonadipose tissues showed a general decline during the progression of gestation. The unexpected pattern of ApN expression in the human fetus may account for the high ApN levels in cord blood and predicts novel roles for ApN during fetal development.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADIPONECTIN (APN) IS an adipocytokine of 30 kDa originally isolated during adipocyte differentiation of 3T3-L1 and 3T3-F442A fibroblasts and from large-scale sequencing of the human adipose cDNA library and exclusively expressed in adipocytes (1). Recent studies suggest an antidiabetic role for ApN, based on the strict and inverse ApN relation with insulin resistance (2). Indeed, in cross-sectional studies, ApN levels negatively correlated with obesity, insulin resistance, dyslipidemia, and cardiovascular disease (3). Moreover, in case-control studies, low ApN seems to be an independent risk factor for development of type 2 diabetes (4, 5). The mechanisms by which ApN may improve insulin resistance are multiple and not completely elucidated, involving increased skeletal muscle fatty acid oxidation, decreased liver free fatty acid influx, and increased glucose uptake in adipocytes and muscle (6, 7, 8). Moreover, by inhibiting myelomonocytic and phagocytic activities as well as TNF{alpha} production by macrophages, ApN exerts antiinflammatory and antiatherogenic roles (9). Accordingly, low ApN levels have been associated with susceptibility to atherosclerosis (10).

Although the antidiabetic and antiatherogenic roles of ApN have been the major focus of research, recent studies suggested that ApN may play a role in intrauterine fetal development, as previously demonstrated for other adipocytokines (11, 12). In particular, the observation that ApN levels in the cord blood of neonates were higher than those measured in the maternal circulation, along with the lack of ApN decline during the early neonatal life, was consistent with a fetal origin of this adipocytokine (11, 12, 13, 14). Therefore, it has been hypothesized that some particular features of the adipose tissue in newborns, including the presence of brown adipose tissue, might be responsible for the high levels of ApN in the fetal circulation (12). However, the presence of a correlation between ApN and adiposity during fetal and neonatal life is still controversial (11, 12, 15).

At the present, no information is available with respect to ApN expression in the fetoplacental unit in humans and animals. In this view, the aim of the study was to confirm the presence of ApN in the fetal circulation; investigate ApN expression in human placenta and fetal tissues by RT-PCR, Western blotting, and immunohistochemistry; and explore changes in the relative ApN expression and distribution during mid- and late gestation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

ApN levels were evaluated in umbilical venous blood obtained from a doubly clamped segment of the cord immediately after fetal extraction before the separation of the placenta from 44 newborns (24 females and 20 males) at the time of elective cesarean section (n = 26) or spontaneous delivery (n = 18) between 30 and 41 wk gestation, together with maternal blood collection (n = 22), in the Department of Obstetrics and Gynecology of the San Paolo Hospital. Fetal birth weight was 3232 ± 624 g (range 1230–4170 g). In 11 newborns, both umbilical arterial and venous blood samples were withdrawn simultaneously, as previously reported (16). The study protocol and collection of blood samples and of fetal and placental tissues were approved by the San Paolo Institute Ethics Committee. All pregnant women gave their informed consent.

Adiponectin assay

Plasma adiponectin was evaluated in maternal and cord blood by human adiponectin ELISA kit, which recognizes both monomeric and oligomeric ApN as declared by the manufacturers (B-Bridge International, Inc., San Jose, CA), as previously described (17). The primary antibody was a monoclonal mouse antihuman ApN. The sensitivity of the assay was 0.37 mg/liter, and the intraassay and interassay coefficients of variation ranged from 5 to 7%.

Fetal tissues

Tissues from fetuses of 14, 16, 25, and 36 wk gestation and placentas and umbilical cords (between 16 and 38 wk gestation) were used. Fetuses from 14, 16, and 25 wk were retrieved after legal voluntary termination of pregnancy for maternal psychiatric disorders, according to the Italian legislation that allows termination of pregnancy for medical reasons up to 25 wk gestation. In these cases, termination was induced by prostaglandin vaginal administration. Fetal death at 36 wk was due to abruptio placentae for unexplained reasons, and pregnancy was terminated by cesarean section due to maternal indications. In all cases, the informed consent of the mother was obtained before procurement of the tissues, in accordance with guidelines outlined by the San Paolo Institute Ethics Committee. Autopsies and sample collections were carried out immediately after delivery, assessing an interval less than 24 h between fetal death and delivery, together with the presence of normal fetal growth and the absence of malformations. For each selected organ, samples were in part stored at –80 C for RT-PCR and Western blot analysis and in part fixed in 10% buffered formalin and paraffin embedded for immunohistochemistry (IHC). The hematoxylin and eosin staining was performed in multiple sections of each sample for morphological diagnostic evaluation. At least two samples from two different fetuses of each fetal tissue at each given trimester of gestation were analyzed in three separate experiments.

mRNA expression analysis by RT-PCR

Total RNA was extracted from fetal tissues using Trizol reagent (Life Technologies Inc., Gaithersburg, MD), as described by the manufacturer. Five micrograms total RNA was reverse transcribed (Promega, Madison, WI) and then subjected to PCR (28 cycles at 94, 58, and 72 C for 45, 45, and 45 sec) using intron-spanning specific primers for human adiponectin gene (GenBank accession no. NM004797) (sense: 5'-CTGGTGAGAAGGGTGAGAAA-3'; antisense: 5'-CTTCTTGAAGAGGCTGACCT-3') to yield a product size of length 350 bp. PCRs were also performed in RNA samples before reverse transcription to exclude DNA contamination. The housekeeping ß-actin gene was used as control in all RT-PCR experiments to assess cDNA quality. The PCR products were separated by 2% agarose gel electrophoresis, stained with ethidium bromide, and the specific bands isolated and sequenced to assure that the bands represented the expected product, using an automated sequencer (PerkinElmer Corp., Norwalk, CT), as previously reported (18).

Western blotting

Western blotting was performed as previously described (19). Briefly, proteins extracted from fetal frozen tissues were quantified using the BCA assay protein (Pierce, Rockford, IL), and 20 µg were resolved by 12% SDS-PAGE and transferred onto nitrocellulose membrane (transfer blot; Bio-Rad Laboratories, Hercules, CA). ApN protein (30 kDa) was detected using a mouse monoclonal antibody to ApN (AX773; Alexis Biochemicals, Lausen, Switzerland) at 1:5000 dilution at room temperature for 1 h and then with a secondary antimouse {gamma}-globulin antibody (Sigma, St. Louis, MO) conjugated to horseradish peroxidase. The membranes were finally treated with chemiluminescent substrate and enhancer (Pico; New England, Biolabs, Beverly, MA).

IHC

IHC was performed as previously described (20, 21). Briefly, formalin-fixed, paraffin-embedded tissue sections were deparaffinized, rehydrated, and rinsed in Tris-buffered saline/Triton X-100 (1:20 in distilled water). Endogenous peroxidase activity was blocked in 3% H2O2 (peroxidase-blocking-reagent; Dako, Carpinteria, CA) for 10 min at room temperature. After washing, tissue sections were incubated with the same mouse monoclonal antibody to ApN used for Western blotting (AX773; Alexis Biochemicals) at 1:500 dilution in Tris-buffered saline/Triton X-100 for 30 min at room temperature. After washing, slides were incubated with SuperBlock reagent (BioGenex, San Ramon, CA) for 20 min at room temperature, followed by a 30-min incubation with poly-horseradish peroxidase (antimouse and antirabbit secondary antibody). Diaminobenzidine was used as chromogen, and the reaction was enhanced by using 0.5% copper sulfate in 1 M NaCl. Sections were finally counterstained with Mayer hematoxylin and mounted. The specificity of the immunoreaction of ApN was tested by omitting the primary antibody and confirmed by the presence and absence of immunostaining in sections of adult tissues in which ApN is known to be (adipose tissue) or not (liver) expressed. Moreover, preadsorption experiments were performed preincubating the antiserum with the soluble recombinant human ACRP30 (Alexis Biochemicals) overnight at 4 C.

Statistics

The results are expressed as mean ± SD. Differences between groups were performed by the Student’s t test with Welch correction, and correlations were examined by linear regression analysis. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Circulating ApN levels in neonates

ApN was detectable in the umbilical venous blood of all 44 newborns delivered between 30 and 41 wk gestation in concentrations ranging from 11.6 to 59.2 mg/liter. Umbilical blood ApN levels were significantly higher, compared with maternal levels (mean ± SD, 31.2 ± 14.1 vs. 8.4 ± 4.0 mg/liter, P < 0.0001) and positively correlated (r = 0.41; P = 0.005) with gestational age at delivery (Fig. 1AGo). Conversely, cord ApN levels as well as the corresponding maternal levels did not show any significant correlation with fetal birth weight (Fig. 1BGo). By measuring ApN levels in both umbilical artery and vein, no significant venoarterial difference was found (27.4 ± 3.9 vs. 24.7 ± 3.1 mg/liter, respectively).



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  		FIG. 1. Circulating ApN levels in umbilical venous blood from 44 neonates delivered between 30 and 41 wk gestation. Cord blood ApN levels were positively correlated with gestational age at delivery (A), whereas they did not show any correlation with fetal birth weight (B). No significant correlation was found with the corresponding maternal levels (C).

 
ApN expression in fetal tissues

In preliminary experiments, we examined the expression of mRNA from fetal tissues at midgestation using RT-PCR. As shown in Fig. 2AGo, mRNA encoding ApN was expressed at apparently lower levels than those expressed in the adult white adipose tissue in skin, skeletal muscle, small intestine, and amniotic membrane samples. Conversely, RT-PCR from other fetal organs, such as liver, heart, lung, placenta, and cord samples, did not reveal ApN transcripts. The identity of ApN mRNA was confirmed by direct nucleotide sequencing.



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  		FIG. 2. RT-PCR and Western blotting analysis for ApN mRNA and protein expression of fetal tissues at midgestation (25 wk; n = 2). A, mRNA encoding ApN was expressed in skin, skeletal muscle, small intestine, and amniotic membrane samples at apparently lower levels than those expressed in the adult white adipose tissue. Conversely, RT-PCR from other fetal organs, such as liver, heart, lung, placenta, and cord samples did not reveal ApN transcripts. The integrity of the mRNA was documented by RT-PCR of the housekeeping gene ß-actin. The identity of ApN mRNA was confirmed by direct nucleotide sequencing. B, Western blotting analysis of the same samples showed ApN protein in all tissues positive for ApN mRNA. Moreover, ApN protein was present at a high level in the placental samples.

 
To demonstrate the expression of both mRNA and associated protein in the various tissues, the same samples were subjected to Western analysis. By this approach, ApN protein was detected in all tissues positive for ApN mRNA as well as in the placental samples (Fig. 2BGo).

To localize the expression of ApN at the cellular level, we performed IHC employing a monoclonal antibody to human ApN. No ApN immunostaining was found in placental and endothelial cells (Fig. 3AGo) obtained from sample preparations (n = 7) of different gestational ages (16–38 wk gestation), consistent with the failure of RT-PCR to detect ApN mRNA. Conversely, a strong immunoreactivity was present within the blood vessel lumina in all placental samples, in agreement with the strong protein signal seen by Western analysis (Fig. 3AGo). The expression in the amniotic epithelium was heterogeneous, with some cells staining intensively and others reacting weakly or not at all (Fig. 3BGo).



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  		FIG. 3. Tissue sections were incubated with ApN-specific antibody (1:500). The immunoreactivity was visualized by diaminobenzidine, positive cells giving a brown color at the site of reaction. In the placenta, ApN immunoreactivity was present in the vessel lumen of the chorionic villous (A; magnification, x600), likely representing high-molecular-weight complex; endothelial cells were negative. In the amniotic membrane (B; magnification, x400), most cells showed an intense positivity for ApN, whereas the underlying mesodermal tissue was negative. An intense staining for ApN was present in the superficial layer of epidermis in fetuses at 14–16 wk gestation (C; magnification, x200). With the progressive maturation and growth of the skin, ApN immunoreactivity localized to basal layers of epidermis and in the underlying dermis (25 wk) (D; magnification, x200). The fetal lens at 14 wk gestation showed a mild and diffuse immunoreactivity (E) that involved the majority of fibers (F; magnification, x400).

 
As far as the fetal tissues were concerned, our initial study examined tissues positive for both ApN mRNA and protein. In agreement with RT-PCR and immunoblotting data, intense ApN immunoreactivity was detected in the skin. By studying tissues from fetuses covering different gestational ages (from 14 to 36 wk gestation), an intense staining for ApN was present in the superficial layer of epidermis in fetuses at 14–16 wk gestation (Fig. 3CGo). With the progressive maturation and growth of the skin, ApN immunoreactivity localized to basal layers of epidermis and in the underlying dermis (25 wk) (Fig. 3DGo). Finally, at late gestation (36 wk), ApN staining was absent in the epidermis and weakly detectable in the dermis.

ApN immunoreactivity was detected in the epithelium and the fibers of the ocular lens at 16 wk (Fig. 3EGo) and confirmed at 25 wk (Fig. 3FGo).

ApN immunopositivity was detected in fibers of skeletal muscles (Fig. 4Go, A and B). The pattern of ApN staining in these tissues changed with the progression of fetal development. Indeed, in fetuses at 16–25 wk, the diaphragm and iliopsoas muscles showed a highly variable pattern of ApN expression, with most intense staining in some fibers and weak or absent signal in others. At term gestation (36 wk), the sarcoplasmatic immunopositivity appeared diffuse and less intense (Fig. 4BGo). During mid- and late gestation, ApN immunoreactivity also localized to smooth muscle fibers, particularly in the wall of the small intestine and the major arterial vessels (Fig. 4Go, C and D).



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  		FIG. 4. ApN immunoreactivity in human fetal tissues of mesodermal origin. At 25 wk gestation (A; magnification, x400), some skeletal muscle fibers of the diaphragm showed an intense staining (arrow), whereas other cells were negative. At 36 wk, ApN immunoreactivity affected homogenously and less intensively almost all skeletal muscle fibers of the iliopsoas (B; magnification, x100) as well as the diaphragm (not shown) and the perineurium. The nervous terminal was negative (arrow). Weak immunoreactivity was detected in smooth muscle cells of the small intestine at 16 wk (arrows in C; magnification, x400). ApN was present in smooth muscle cells (D; magnification, x100) of the arterial walls at 36 wk (arrow). As in adult life, adipose tissue showed intense immunoreactivity for ApN at 36 wk (E; magnification, x200); the star shows a negative nervous terminal and the arrow the positive surrounding connective tissue. The heart, liver, and lung (F; magnification, x40) were negative in all gestational ages.

 
ApN immunoreactivity was present in some mesenchymal tissues. In particular, ApN was expressed in the sclera of the eye (Fig. 3EGo) and in the perineurium, the fibrous connective covering of the nervous terminals (Fig. 4Go, B and E) at all gestational weeks and in the connective tissue surrounding the skeletal muscles and the kidney (fibroelastic capsule) in fetuses at 25–36 wk (data not shown).

As far as the presence of ApN in fetal adipose tissue was concerned, in fetuses at 14 wk, intense ApN immunoreactivity was detected in a small group of brown adipocytes located in the retrobulbar space (data not shown). The appearance of the adipose tissue during the progression of fetal development was associated with intense ApN immunoreactivity, which was evident along the dorsal body wall and around the iliopsoas muscle (25 wk) and in the sc deposits at later gestational age (36 wk) (Fig. 4EGo). At that age, ApN immunoreactivity was not detectable in the dorsal body wall fat.

Fetal tissues negative for both ApN mRNA and protein at Western blot analyses, such as liver, heart, and lung, did not show any ApN staining at IHC (Fig. 4FGo).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrates for the first time that ApN gene expression and mature ApN protein are present in a number of tissues of the human fetus, at least in mid- and late gestation. This novel pattern of ApN expression provides answers to previous unexplained observations and discloses new roles for this adipocytokine. In fact, ApN expression in fetal tissues may account for ApN hypersecretion observed in neonatal life. Indeed, in accordance with previous studies on newborns at term (11, 12, 13, 14), high levels of ApN, significantly exceeding those present in the maternal circulation, were detected in cord blood as early as 30 wk gestation. Cord blood ApN levels significantly increased with gestational age at birth, although this increase was not correlated with the neonate birth weight, in contrast with previous reports (12, 15). This discrepancy may reflect differences in gestational ages or assay procedures. In particular, the lack of correlation between ApN and birth weight in our series may be related to the small number of preterm infants because the association between fetal ApN levels and birth weight has been reported only in preterm infants (15). Moreover, this study demonstrates that the placenta was not a source for ApN, at least in mid- and late gestation. Therefore, although the placenta produces and releases other adipocytokines, such as leptin and resistin (22, 23), this tissue was not responsible for the hyperadiponectinemia observed in neonates. This is in agreement with previous studies demonstrating the persistence of ApN hypersecretion a few days postpartum, in contrast with the dramatic decline of leptin levels (12). The finding of absence of significant venous-arterial difference in umbilical artery and vein of term neonates is consistent with a poor, if any, placental contribution to ApN concentration in fetal blood.

Moreover, the pattern of ApN expression during fetal life was markedly different from that of adulthood (1) because ApN was expressed in several tissues derived from distinct embryonic germ layers. As expected, ApN was present in adipocytes, and the pattern of ApN expression followed the development of the adipose tissue during the progression of fetal growth. In fact, ApN was detected in the adipocytes of brown adipose tissue in the retroocular space of the orbit of early fetus (14 wk gestation, the earliest time point studied) and subsequently along the dorsal body wall, in which brown fat cells are located during human fetal development. The appearance of white adipose tissue in the perimuscular and sc deposits during fetal growth progression was accompanied by a strong ApN immunoreactivity in these tissues and the disappearance of ApN in the dorsal body wall. This is in line with the notion that in human neonates the fat, which represents around 12–14% of body weight (24), is mostly found in the form of white adipose tissue, and its accretion occurs essentially during the last trimester of intrauterine life (25).

In addition to adipocytes, other tissues of mesodermic origin, such as skeletal muscle fibers (Fig. 4BGo), smooth muscle cells of small intestine and arterial walls (Fig. 4Go, C and D), and connective tissues, expressed ApN. The finding of ApN expression in mesenchymal-deriving cells is in line with some in vitro evidences indicating that rat adipocytes differentiating from 3T3-L1 fibroblasts (1), as well as human mesenchymal stem-cells, may express ApN (26). Moreover, it has been recently reported that in vitro cultured human skeletal myotubes expressed ApN mRNA under the influence of ApN itself (27). A possible involvement of ApN in the control of mesenchymal cell proliferation and differentiation is further suggested by the phenotype of the ApN knockout mice, which, in the absence of evident anomalies in tissue development at birth and up to 30 wk of age, showed increased neointimal thickening of injured arteries due to proliferation of smooth muscle cells (28). It is tempting to speculate that the expression of ApN in mesenchymal-deriving cells may initiate an autocrine-paracrine loop involved in the control of cell proliferation and differentiation together with the maintenance of insulin sensitivity.

The expression of ApN in tissues of ectodermal origin, i.e. the epidermis and lens, is an unexpected finding. Although it is difficult at the present time to predict roles for ApN in these tissues, the observation that insulin, along with other growth factors, is involved in the differentiation of both fetal lens and epidermis, suggests that ApN might participate in this signaling pathway during fetal life (29, 30).

The distribution of ApN expression among the single cells or different cellular layers of a single tissue changed dramatically during development. The skin and skeletal muscles provide interesting examples. During midgestation, ApN was expressed exclusively in the outer layer of the skin (Fig. 3CGo), whereas in the following gestational ages, ApN immunostaining was confined to the basal-layer epithelial cells and the underlying connective tissue of the derma (Fig. 3DGo). Similarly, at midgestation ApN was highly expressed in some skeletal muscle fibers and absent in others (Fig. 4AGo), whereas a more homogeneous distribution, associated with a progressive decline with the gestation progression, was observed (Fig. 4BGo). This decline was associated with the increase of white adipose tissue, likely accounting for the high fetal ApN levels observed in late gestation.

Finally, until now research on ApN levels in neonates has been mainly focused on ApN relation to birth weight in offspring of healthy and diabetic mothers (11, 12). Taking into consideration the wide expression of ApN reported here, it would be of interest to investigate cord blood ApN levels in the presence of intrauterine development abnormalities.

In conclusion, we have demonstrated a novel and unexpected pattern of ApN expression in human fetal tissues that dramatically differs from the adult. This may reflect novel roles for ApN in the fetal differentiation and growth that may be redundant in the adult, as it has been reported for other factors (31). Future studies should explore the mechanisms by which ApN might regulate tissue differentiation and growth during fetal development and define the factors conditioning changes in ApN expression in fetal and postnatal life.


   Footnotes
 
First Published Online December 28, 2004

Abbreviations: ApN, Adiponectin; IHC, immunohistochemistry.

Received August 4, 2004.

Accepted December 20, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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