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

Abstract

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 the non-pregnant state. The product of the imprinted Delta-like homologue 1 gene (DLK1) is an endocrine signaling molecule that reaches a high concentration in the maternal circulation during late pregnancy. By utilising murine 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) from pathologically small infants in a human cohort. Therefore measurement of DLK1 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.

Genomic imprinting, growth and maternal–fetal interactions

“…Manipulation of Dlk1 dosage has the expected effect on circulating leptin levels: Dlk1 null mice have elevated leptin and Dlk1-TG have reduced levels. However, despite this, food intake is not altered by either genetic manipulation Cleaton et al, 2016), suggesting impaired leptin sensitivity.…”

“…In addition, although Dlk1 null mothers enter pregnancy with increased adipose stores, they gain less adipose mass during pregnancy than wild-type mothers. Altogether, females without a functional copy of Dlk1 invest more resources in pregnancy, suggesting that the normal role for Dlk1 in female reproduction is to decrease nutrient allocation (Cleaton et al, 2016).…”

“…Dlk1 is a paternally expressed gene encoding a single-pass transmembrane protein that can be cleaved to produce a soluble form that circulates in the blood . Dlk1 expression levels in the embryo are positively correlated to embryonic mass in the second half of gestation (Cleaton et al, 2016). Dlk1 deletion causes growth retardation (Cleaton et al, 2016;Moon et al, 2002) and overexpression causes overgrowth independently of the placenta (da Rocha et al, 2009).…”

“…Dlk1 expression levels in the embryo are positively correlated to embryonic mass in the second half of gestation (Cleaton et al, 2016). Dlk1 deletion causes growth retardation (Cleaton et al, 2016;Moon et al, 2002) and overexpression causes overgrowth independently of the placenta (da Rocha et al, 2009). The signalling pathway by which DLK1 acts has yet to be elucidated.…”

“…The signalling pathway by which DLK1 acts has yet to be elucidated. However, DLK1 from the fetus is secreted into the maternal circulation and acts to modify the pregnancyspecific response to nutrient restriction (Cleaton et al, 2016).…”