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Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene.

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Lopez-Tello, Jorge 
Yong, Hannah EJ 
Sandovici, Ionel 
Dowsett, Georgina KC 
Christoforou, Efthimia R 

Abstract

Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health.

Description

Keywords

fetal programming, genomic imprinting, glucose, hormones, insulin-like growth factor 2, metabolism, placenta, pregnancy, prolactin, Animals, Female, Mice, Pregnancy, Cell Communication, Homeostasis, Hypoglycemic Agents, Insulin Resistance, Placenta, Insulin-Like Growth Factor II, Genomic Imprinting

Journal Title

Cell Metab

Conference Name

Journal ISSN

1550-4131
1932-7420

Volume Title

35

Publisher

Elsevier BV
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/H003312/1)
Medical Research Council (MC_UU_12012/4)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (208363/Z/17/Z)
Wellcome Trust (220456/Z/20/Z)
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/5)
Medical Research Council (MC_PC_12012)
British Heart Foundation (RG/17/12/33167)
Medical Research Council (MR/R022690/1)
MRC (MC_UU_00014/4)