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Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction.

Accepted version



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Cleaton, Mary AM 
Dent, Claire L 
Howard, Mark 
Corish, Jennifer A 
Gutteridge, Isabelle 


Pregnancy is a state of high metabolic demand. Fasting diverts metabolism to fatty acid oxidation, and the fasted response occurs much more rapidly in pregnant women than in non-pregnant women. The product of the imprinted DLK1 gene (delta-like homolog 1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By using mouse models with deleted Dlk1, we show that the fetus is the source of maternal circulating DLK1. In the absence of fetally derived DLK1, the maternal fasting response is impaired. Furthermore, we found that maternal circulating DLK1 levels predict embryonic mass in mice and can differentiate healthy small-for-gestational-age (SGA) infants from pathologically small infants in a human cohort. Therefore, measurement of DLK1 concentration in maternal blood may be a valuable method for diagnosing human disorders associated with impaired DLK1 expression and to predict poor intrauterine growth and complications of pregnancy.



Adaptation, Physiological, Animals, Biomarkers, Calcium-Binding Proteins, Case-Control Studies, Cohort Studies, Female, Fetal Growth Retardation, Fetus, Gestational Age, Humans, Infant, Newborn, Infant, Small for Gestational Age, Intercellular Signaling Peptides and Proteins, Mice, Pregnancy, Pregnancy Complications

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Nat Genet

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Springer Science and Business Media LLC
Medical Research Council (MR/J001597/1)
Stillbirth and Neonatal Death Society (SANDS) (JE/DICT4/97771/14)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Medical Research Council (G1100221)
Wellcome Trust (095606/Z/11/Z)
Medical Research Council (MR/K021133/1)
Medical Research Council (G1100221/1)
M.A.M.C. was supported by a PhD studentship from the Cambridge Centre for Trophoblast Research. Research was supported by grants from the MRC (MR/J001597/1 and MR/L002345/1), the Medical College of Saint Bartholomew's Hospital Trust, a Wellcome Trust Investigator Award, EpigeneSys (FP7 Health-257082), EpiHealth (FP7 Health-278414), a Herchel Smith Fellowship (N.T.) and NIH grant RO1 DK89989. The contents are the authors' sole responsibility and do not necessarily represent official NIH views. We thank G. Burton for invaluable support, and M. Constância and I. Sandovici (University of Cambridge) for the Meox2-cre mice. We are extremely grateful to all of the participants in the Pregnancy Outcome Prediction study. This work was supported by the NIHR Cambridge Comprehensive Biomedical Research Centre (Women's Health theme) and project grants from the MRC (G1100221) and Sands (Stillbirth and Neonatal Death Charity). The study was also supported by GE Healthcare (donation of two Voluson i ultrasound systems for this study) and by the NIHR Cambridge Clinical Research Facility, where all research visits took place.