Fetal programming of human energy homeostasis brain networks: Issues and considerations

Abstract

Summary In this paper, we present a transdisciplinary framework and testable hypotheses regarding the process of fetal programming of energy homeostasis brain circuitry. Our model proposes that key aspects of energy homeostasis brain circuitry already are functional by the time of birth (with substantial interindividual variation); that this phenotypic variation at birth is an important determinant of subsequent susceptibility for energy imbalance and childhood obesity risk; and that this brain circuitry exhibits developmental plasticity, in that it is influenced by conditions during intrauterine life, particularly maternal–placental–fetal endocrine, immune/inflammatory, and metabolic processes and their upstream determinants. We review evidence that supports the scientific premise for each element of this formulation, identify future research directions, particularly recent advances that may facilitate a better quantification of the ontogeny of energy homeostasis brain networks, highlight animal and in vitro‐based approaches that may better address the determinants of interindividual variation in energy homeostasis brain networks, and discuss the implications of this formulation for the development of strategies targeted towards the primary prevention of childhood obesity.

Maternal pre-pregnancy body mass index is associated with newborn offspring hypothalamic mean diffusivity: a prospective dual-cohort study

“…The current study did not collect or consider several developmentally important maternal ligands including the feeding-related hormones leptin [46] and ghrelin [47]. Further, future efforts should explore the influence of these and other placental, metabolic, inflammatory, and stress factors [20] and focus on their combined and interactive role in the intergenerational transmission of obesity pathway. DTI parameters, including MD, result from the modeling of diffusion processes that are non-specific to the cellular processes that underlie signal variation [48].…”

“…Animal models suggest that the HTH exhibits developmental plasticity during the fetal period as it develops in the context of, and adapts to, variation in maternal overnutrition [13][14][15][16][17][18][19][20], which represents a state of excess maternal nutritional stores (e.g., adipocytes, circulating metabolic ligands) and their associated milieu (e.g., inflammation) from the perspective of the developing fetus. Fetal adaptations to maternal overnutrition have been shown to then influence postnatal metabolism and growth.…”

“…Therefore, in the current study, we focus on the newborn brain, when the HTH has not yet been influenced by the postnatal environment. Furthermore, in the current study, we use maternal prepregnancy BMI as a surrogate measure of overnutrition that is associated with broad changes in maternal-placental-fetal metabolic, inflammatory, and endocrine biology [20] during pregnancy.…”

Maternal free fatty acid concentration during pregnancy is associated with newborn hypothalamic microstructure in humans

“…Finally, the HTH is well established to be the primary central regulator of energy homeostasis. However, there are several extrahypothalamic brain systems (e.g., interoception, salience, reward) with demonstrated relevance in the context of both maternal exposures during pregnancy and offspring obesity risk (44). Although the current study was focused on testing a hypothesis‐based translation of experimental data from the animal literature, large‐scale longitudinal developmental neuroimaging studies such as the upcoming HEALthy Brain and Child Development (45) study represent the ideal platform for conducting a more discovery‐based approach to identifying key extrahypothalamic brain systems in the context of the fetal programming of obesity.…”

Parental body mass index and offspring childhood body size and eating behaviour: causal inference via parental comparisons and extended children of twins structural equation modelling

“…Numerous animal studies purport to provide evidence in favour of the developmental overnutrition hypothesis (9). Potential biological mechanisms have been elucidated ( Figure 1b ) (5, 9), including a putatively key role for the programming of offspring appetite via energy homeostasis brain networks (10). In humans, child appetite traits are associated with the child ‘s own BMI (11), and with maternal overweight/obesity (12).…”