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Abundance of circulating preadipocyte factor 1 in early life.
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MedLine Citation:
PMID:  22338099     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Soluble preadipocyte factor 1 (Pref-1) inhibits adipocyte differentiation. We tested whether circulating levels of soluble Pref-1 are higher in smaller fetuses.
RESEARCH DESIGN AND METHODS: We performed longitudinal assessments of circulating Pref-1 in infants born appropriate for gestational age (AGA) or small for gestational age (SGA) and also in late-gestational women and in newborns on days 2 and 3.
RESULTS: At birth, Pref-1 levels were ~100-fold higher than in adults, being in SGA fetuses ~50% higher than in AGA fetuses. By age 4 months, Pref-1 had reached near-adult levels and the original AGA versus SGA difference had disappeared. Pref-1 levels were low in late-gestational women and were still elevated in newborns.
CONCLUSIONS: Pref-1 is abundantly present in the fetus, is higher in SGA than in AGA fetuses, and is likely to be of fetal origin. We speculate that Pref-1 in early life contributes to variation in postnatal adipocyte numbers, in the subsequent expandability of adipose tissue, and thus in the susceptibility to diabetes in later life.
Francis de Zegher; Marta Díaz; Giorgia Sebastiani; Ana Martín-Ancel; David Sánchez-Infantes; Abel López-Bermejo; Lourdes Ibáñez
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-14
Journal Detail:
Title:  Diabetes care     Volume:  35     ISSN:  1935-5548     ISO Abbreviation:  Diabetes Care     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-23     Completed Date:  2012-08-09     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  7805975     Medline TA:  Diabetes Care     Country:  United States    
Other Details:
Languages:  eng     Pagination:  848-9     Citation Subset:  IM    
Department of Woman and Child, University of Leuven, Leuven, Belgium.
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MeSH Terms
Age Factors
Birth Weight / physiology
Fetus / metabolism
Follow-Up Studies
Gestational Age
Infant, Newborn / blood*
Infant, Small for Gestational Age / blood
Intercellular Signaling Peptides and Proteins / analysis,  blood*,  metabolism
Membrane Proteins / analysis,  blood*,  metabolism
Reg. No./Substance:
0/DLK1 protein, human; 0/Intercellular Signaling Peptides and Proteins; 0/Membrane Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-ta): Diabetes Care
Journal ID (iso-abbrev): Diabetes Care
Journal ID (hwp): diacare
Journal ID (pmc): dcare
Journal ID (publisher-id): Diabetes Care
ISSN: 0149-5992
ISSN: 1935-5548
Publisher: American Diabetes Association
Article Information
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© 2012 by the American Diabetes Association.
Received Day: 12 Month: 10 Year: 2011
Accepted Day: 19 Month: 12 Year: 2011
Print publication date: Month: 4 Year: 2012
Electronic publication date: Day: 13 Month: 3 Year: 2012
Volume: 35 Issue: 4
First Page: 848 Last Page: 849
PubMed Id: 22338099
ID: 3308291
Publisher Id: 1990
DOI: 10.2337/dc11-1990

Abundance of Circulating Preadipocyte Factor 1 in Early Life
Francis de Zegher, PHD1
Marta Díaz, PHD23
Giorgia Sebastiani, MD23
Ana Martín-Ancel, MD4
David Sánchez-Infantes, PHD23
Abel López-Bermejo, PHD5
Lourdes Ibáñez, PHD23
1Department of Woman and Child, University of Leuven, Leuven, Belgium
2Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
4Department of Neonatology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
5Department of Pediatrics, Girona Institute for Biomedical Research, Dr. Josep Trueta Hospital, Girona, Spain
Correspondence: Corresponding author: Lourdes Ibáñez,

The number of subcutaneous adipocytes wherein fat can be stored during adulthood is essentially determined in two windows of adipogenesis, namely, fetal life and puberty (1,2). For example, in monozygotic twins discordant for growth before birth, the smaller twin continues to have a lower number of subcutaneous adipocytes after birth (3). It is still poorly understood how a transient restraint of fetal growth can be linked to a persistent lowering of adipocyte number. We propounded that one of the potential links is a downregulation of adipogenesis in a critical window of growth restraint before birth. In a first test of this concept, we studied at birth whether circulating preadipocyte factor 1 (Pref-1) is higher in smaller fetuses. Pref-1 is a transmembrane protein that is encoded by an imprinted (paternally expressed) gene on chromosome 14q32 and that contains an extracellular domain with epidermal growth factor–like repeats; juxtamembrane cleavage generates a soluble 50-kDa form, which is the Pref-1 form that inhibits adipocyte differentiation by upregulating Sox9 in preadipocytes (4,5). Thus far, the circulating levels of Pref-1 have not been studied in human fetuses, newborns, infants, or pregnant women.


Pref-1 was measured longitudinally (at birth and at 4 months) in serum from 72 infants (42 born appropriate for gestational age [AGA] [19 girls and 23 boys] and 30 born small for gestational age [SGA] [16 girls and 14 boys]) who had been recruited into a study that was initiated in 2007 and that assesses longitudinally the endocrine-metabolic state and the body composition of SGA infants compared with breastfed AGA control subjects across the first postnatal years (6,7). For the present substudy focusing on Pref-1, specific inclusion criteria were as follows: 1) birth at Hospital Sant Joan de Déu after an uncomplicated, term (38–40 weeks), and singleton pregnancy (no maternal hypertension and no gestational diabetes); 2) birth weight between 3.0 and 3.8 kg for AGA control subjects (birth weight range between −1 and +1 SD), and birth weight <2.6 kg for SGA infants (below −2 SD); 3) cord serum available to measure Pref-1; and 4) written informed consent in the Catalan language. Specific exclusion criteria were complications at birth (need for resuscitation or for parenteral nutrition), congenital malformations, or an extremely low birth weight (below −3.0 SD).

Gestational age was calculated according to the last menses and confirmed by first-trimester ultrasound. The prevalence of delivery by caesarean section was 12%. A total of 17 mothers smoked during pregnancy; they delivered 7 AGA and 10 SGA infants.

Pref-1 was also measured in 11 healthy AGA newborns (mean birth weight 3.3 kg) sampled on postnatal day 2 or 3 (mean age 44 h [range 30–57]) and from 18 women in late gestation (mean 35 weeks [32–38]) who subsequently delivered healthy infants (mean birth weight 3.3 kg [2.7–4.0]) after uncomplicated singleton pregnancies (mean duration 39 weeks [37–41]).

Body weight was measured at birth with a beam balance (Seca, Hamburg, Germany). Blood from the longitudinally studied infants was sampled at birth (from the umbilical cord before placental separation) and in the prefeeding state at age 4 months. All samples were centrifuged and frozen at −80°C until analysis. Body composition was assessed by absorptiometry at age 2 weeks (mean ± SEM 17 ± 1 days) with a Lunar Prodigy, coupled to Lunar software (version 3.4/3.5; Lunar, Madison, WI) adapted for infants (6,7). Soluble 50-kDa Pref-1 was assessed by ELISA (R&D Systems, Minneapolis, MN) (intra- and interassay coefficients of variation 3.6 and 6.2%, respectively; detection limit 0.01 μg/L).

Statistical analyses were performed using SPSS 12.0 (SPSS, Chicago, IL). Results are expressed as means ± SEM. Comparisons between groups were performed by t test. Skewed data were log transformed prior to comparison. P < 0.05 was considered significant.

All assessments were approved by the institutional review board of Barcelona University Hospital. Written (parental) consent was an inclusion criterion.


Pref-1 levels in late-gestational women were 0.7 ± 0.1 μg/L (range 0.02–1.6), which were comparable with those reported in nonpregnant women (8). Circulating Pref-1 was readily detectable in all infants. Pref-1 levels were comparable in girls and boys, and the results of both sexes were therefore pooled (Table 1).

At birth, Pref-1 levels ranged from 6 to 100 μg/L and were thus one to two orders of magnitude higher than in the maternal circulation. Pref-1 levels were ~50% higher in SGA than in AGA fetuses. By age 4 months, Pref-1 concentrations had reached a near-adult level and the original AGA versus SGA difference in Pref-1 levels had disappeared. No close associations were observed between Pref-1 concentrations and body composition either at birth or at age 4 months. On day 2 or 3, serum concentrations of Pref-1 in AGA newborns were still 14 ± 2 μg/L (range 8–26), suggesting that prenatal Pref-1 has a fetal rather than a placental or maternal origin.


In the first months after birth, SGA infants prioritize the recovery of lean mass to that of fat mass and of bone mineral content. Soluble Pref-1 is thought to reduce adipogenesis as well as bone formation by inhibiting the differentiation of multipotent mesenchymal cells into adipocytes, chondrocytes, and osteoblasts (5,9,10). Here, we show that Pref-1 is abundantly present in the circulation of the human fetus and that SGA fetuses have higher Pref-1 levels than do AGA control subjects.

Growth restraint in early life is a major risk factor for diabetes in later life (11,12). Our finding that fetal growth restraint is associated with markedly high Pref-1 levels suggests that Pref-1 may be among the mediators of a reduced adipocyte differentiation in growth-restrained fetuses, and thus of a reduction in their life-long lipid-storage capacity and also of their adult vulnerability to metabolic disease, once lipid storage becomes an issue.

In conclusion, Pref-1 is abundantly present in the circulation of the human fetus and is likely to be of fetal rather than maternal or placental origin. Circulating Pref-1 levels are higher in SGA than in AGA fetuses.


This study was supported by a grant from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PI08/0443). F.d.Z. is a clinical investigator supported by the Clinical Research Council of the Leuven University Hospitals and by the University of Leuven (OT-04-35). G.S. is a predoctoral investigator of Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (FI06/00425). A.L.-B. is a clinical investigator of the I3 Fund for Scientific Research (Ministry of Science and Innovation, Madrid, Spain).

No potential conflicts of interest relevant to this article were reported.

F.d.Z. wrote the manuscript. M.D. researched data and reviewed and edited the manuscript. G.S. researched data and contributed to discussion. A.M.-A. and D.S.-I. researched data. A.L.-B. and L.I. contributed to discussion and reviewed and edited the manuscript. L.I. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors thank Luis del Río, MD, and Silvana di Gregorio, MD, from Centro Médico CETIR, Barcelona, Spain, for performing the absorptiometry measurements.

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[TableWrap ID: T1] Table 1 

Results from AGA versus SGA infants

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    • Cardiovascular and Metabolic Risk

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