Maternal obesity and the embryonic rewiring of feeding circuits: Beyond the hypothalamus

Maternal obesity disrupts fetal hypothalamic development by inducing structural changes in feeding circuits, such as reduced hypothalamic precursor proliferation, blunted energy-status sensing, and aberrant wiring of melanocortin pathways, ultimately promoting long-term obesity risk in offspring. Although this hypothalamic reprogramming has dominated research, emerging evidence supports a broader, distributed model involving both brainstem interoceptive circuits and mesocorticolimbic reward-control systems. Maternal obesity is associated with impaired white matter development in offspring, as well as compromised functional connectivity, abnormal orexigenic and anorexigenic signaling, hypothalamic inflammation, and epigenetic alterations in neurodevelopmental genes. Human neuroimaging studies demonstrate altered network connectivity in neonates associated with maternal adiposity. However, the mechanism through which dysregulated maternal signals ultimately reach and reprogram the developing brain remains largely elusive. The present review aims to elucidate the mechanisms by which maternal overnutrition drives the embryonic rewiring of feeding circuits beyond the hypothalamus, highlighting the susceptibility of these extra-hypothalamic neural networks to obesogenic programming. Future research should prioritize investigating the effects of maternal obesity on fetal cytoarchitecture and function in feeding-related neuroanatomical circuits, including brainstem interoceptive nuclei and mesocorticolimbic reward-control pathways. Elucidating these developmental neuro-metabolic changes may offer the opportunity to establish early intervention measures for preserving offspring metabolic health.