Fetal Liver Blood Flow Distribution: Role in Human Developmental Strategy to Prioritize Fat Deposition versus Brain Development

Abstract

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.

Association of early childhood abdominal circumference and weight gain with blood pressure at 36 months of age: secondary analysis of data from a prospective cohort study

“…Indeed, we have previously demonstrated that higher fetal liver blood flow is strongly correlated with greater fat mass at birth and at 4 years, indicating that influences on body composition operate very early in life 24. Our data show that changes in abdominal circumference during the first 6 months and in the third year of life are associated with systolic and diastolic blood pressure.…”

The Placental Exposome: Placental Determinants of Fetal Adiposity and Postnatal Body Composition

“…It is now possible to make in utero measurements of fetal and placental blood flow and growth [50,51]. The use of stable isotopes provides an important means to study placental transfer in vivo avoiding the drawbacks of ex vivo systems [52] when coupled with increasingly powerful biochemical and molecular approaches to study plasma and tissues samples [25,53].…”

“…An example of the use of these techniques in a longitudinal study comes from the Southampton Women's Survey, where fetal growth measures have been determined by ultrasound and related to placental gene expression and post-natal bone density [54]. Other studies have related maternal body composition and placental weight to fetal blood flow distribution in the fetus [50,55]. Increased fetal liver blood flow is associated with fetal macrosomia in the third trimester [51] and greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth and at age 4 years [50].…”

“…Other studies have related maternal body composition and placental weight to fetal blood flow distribution in the fetus [50,55]. Increased fetal liver blood flow is associated with fetal macrosomia in the third trimester [51] and greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth and at age 4 years [50]. In the Generation R study, analysis of placental haemodynamics demonstrated associations between maternal lifestyle characteristics and placental resistance indices [56].…”

Prospective association of fetal liver blood flow at 30 weeks gestation with newborn adiposity

“…When oxygen is limited, fetal adaptations prioritize brain growth, irrespective of whether other essential nutrients are limited or not. 19,20 However, when oxygen is adequate but other essential nutrients are limited, fetal adaptations prioritize adipose tissue accretion, 21,22 presumably because adipose tissue constitutes a key buffer against limited nutrient supply, particularly to meet the brain’s energy requirements during early postnatal life. 23 Indeed, the infant brain requires and utilizes approximately 40–60% of the infant’s total energy needs, 24 and adipose tissue-derived ketone bodies can provide as much as 25% of this requirement.…”