We previously showed that distribution of nutrient-rich placental blood between liver and the ductus venosus liver shunt, controlled by haemodynamic 
and neuro-hormonal mechanisms 
is affected by maternal thinness 
, which itself is linked to dyslipidemia, impaired glucose tolerance and susceptibility to metabolic disease in later life in the offspring 
. summarises the principal findings of the present study. Variations in the distribution of nutrient-rich placental blood associated with placental size and fetal adiposity lead us to speculate about a possible mechanistic framework integrating our observations (). In this we hypothesise that the balance between fetal nutrient demand and materno-placental nutrient supply may alter the distribution of umbilical venous blood flow, with implications for fetal body composition. Umbilical venous blood flow distribution is related to nutritional status, with so-called ‘brain-sparing’ mechanisms 
coming into play only if placental supply does not meet fetal demand for essential nutrients that cannot be synthesised by the fetal liver, such as oxygen 
. This tends to occur when the fetal demand is relatively high (e.g. male fetus, ) and the supply capacity and umbilical venous blood flow is constrained (e.g. small placenta, ). However, when the mother has a poor diet or is thin it is the supply of conditionally essential nutrients that is limiting and the strategy is to prioritize liver blood flow in these circumstances (as reported previously) 
, enabling hepatic nutrient interconversions and the synthesis of the fatty acids required for fat deposition. Conditionally essential nutrients are those essential for metabolism and growth, but which can be generated by hepatic conversion of other nutrients if the dietary supply is inadequate 
; examples include amino acids such as glycine and long chain fatty acids such as docosahexaenoic acid. Fetal liver blood and fat deposition () is prioritized in utero
as adipose tissue is needed for neonatal thermoregulation and as a buffer for brain development if there are subsequent periods of limited nutrient supply. In keeping with this model, we have recently shown that increased fetal liver blood flow is associated with fetal macrosomia in the third trimester 
. Our model () further hypothesises that, in environments less affluent than those now prevalent in developed populations, facilitated placental transfer mechanisms have evolved for glucose and other nutrients to enable materno-placental nutrient supply to meet fetal nutrient demand, resulting in optimal fetal body composition. However, we propose that in circumstances of nutrient excess these mechanisms also lead to prenatal fat deposition, reflected in the association we found between maternal adiposity and neonatal fat mass ().
Principal findings of the study.
Suggested developmental strategies associated with imbalances between fetal nutrient demand and materno-placental nutrient supply.
We recruited children from a free-living population cohort and used objective measures of postnatal adiposity. However, there are several limitations to our study. Intrauterine ultrasound measurements are prone to a certain amount of error, but the Doppler blood flow measurements were made by a single experienced operator (GH) following internationally agreed guidelines and repeatability was good. Secondly, we were only able to follow up a proportion of the original group at age 4 years, but the children who underwent the 4 year assessment did not differ in terms of their fetal liver blood flow or adiposity at birth from those who did not. Moreover, as the analysis is based on internal comparisons it is difficult to envisage how this would have spuriously shown an association between fetal liver blood and postnatal adiposity. Thirdly, a range of potential confounders were considered but residual confounding cannot be excluded. Fourthly, we used DXA to measure fat mass. This technique is associated with technical limitations in children and is hampered by their tendency to move. However, we used specific paediatric software, and movement artefact was modest and uniform across the cohort; those few children with excessive movement were excluded from the analysis. Fifthly, the association between high ductus venosus liver shunting and thinner neonatal subscapular skinfold thickness was only seen above a threshold and the possibility of an artefactual finding must be born in mind. The clear, graded association between fetal liver blood flow and adiposity was not seen for ductus venosus shunting; we speculate that this may be the result of a direct link between hepatic perfusion and adipose tissue deposition as opposed to increased ductus venosus shunting only occurring above a threshold of constrained fetal nutrient supply.
Our proposal that alterations in fetal blood flow distribution may have wider implications is supported by experimental studies in animals showing that hepatocyte gene expression can be altered by changes in fetal liver blood flow 
and by maternal diets with a low protein content 
. Maternal low protein diets have also been shown to alter epigenetic processes in hepatocytes in the offspring 
, with permanent consequences including altered liver carbohydrate and fat metabolism 
and a predisposition to adult obesity and reduced lifespan 
. Moreover, a reduction in liver glucocorticoid receptor and fibrinogen gene expression caused by a low protein maternal diet was confined to the left hepatic lobe 
; in circumstances of high ductus venosus liver shunting there is differential perfusion of the right and left hepatic lobes, with preferential perfusion of the left hepatic lobe by umbilical blood 
Adiposity in childhood is associated with the risk of adult obesity 
. The association of fetal liver blood flow with fat mass not only in the newborn but also at four years of age in this cohort with birth weights within the normal range is thus of concern in relation to obesity and the risk of associated diseases later in life.
Our results lead us to propose that in the normal human fetus a developmental strategy of allocating umbilical venous blood flow to the liver, to overcome an inadequate supply of conditionally essential nutrients and prioritize fat deposition, brings with it important metabolic consequences which can have lasting effects on body composition. In the human infant, the demands of a big brain have not only led during evolution to the development of fetal responses which preserve nutrient delivery to the brain when the materno-placental nutrient supply of essential nutrients cannot meet fetal nutrient demand, but also to a need to deposit fat in order to buffer brain development during periods of nutrient restriction in postnatal life. We hypothesise that evolution of this strategy has brought with it a predisposition to obesity and later diabetes in contemporary societies with abundant nutrition in later postnatal life 
. Because the strategy is a fundamental aspect of human biology, it occurs to a degree across the range of infant growth and development, and could be an important determinant of the risk of obesity at the population level. Furthermore the strategy is compounded by the evolution of facilitated placental transfer mechanisms for glucose and other nutrients which now also lead to fetal adipose tissue deposition in the circumstance of nutrient excess associated with maternal adiposity now prevalent in developed communities. Although our hypothesis is supported by experimental data from animal studies, direct causality cannot be inferred from observational data. Nonetheless the findings add to an increasing evidence base suggesting that particular developmental influences acting before birth play important roles in the human propensity to deposit fat; understanding this fundamental biology in early life may be valuable in the prevention of obesity and early detection of those at particular risk.