Beyond Deterministic Fetal Programming: Intrauterine Exposures and the Multifactorial Origins of Adiposity

Excess adiposity is not a recently developed problem but has existed since at least the upper Paleolithic, allowing evolutionary selection pressures to adapt the physiology of the pregnant woman and the feto-placental unit for maternal and fetal protection. Disturbances of the intrauterine environment, in particular metabolic derangements early in pregnancy, such as in women with diabetes and/or obesity, may lead to fetal hyperinsulinaemia. This often results in neonatal adiposity, which may in turn increase the risk for childhood adiposity. In this review, we summarize evidence on possible underlying mechanisms and factors that moderate the association between in utero exposure and childhood adiposity focusing on pregnancies in women with diabetes or obesity. We conclude that in humans causal evidence is missing for fetal programming of adiposity in the deterministic sense as often used and propose a more opportunistic framework. A variety of postnatal exposures and their interaction with the individual's genetic background contribute to the multifactorial problem of excessive adiposity, which may be further compounded by varying sensitivity to environmental perturbations depending on the developmental stage of the individual. We identify research gaps and describe future studies to generate causal evidence necessary.