A mother’s obesity during pregnancy is well-recognised for its ability to elevate her offspring’s risk of obesity and the metabolic syndrome. Because the physiology of the mother and her offspring interact most intimately during gestation, we have been characterising the changes that take place to the fetal hypothalamus during its development in an obese mother.
Female C57B/6J mice were fed a high-fat diet (45% kcal from fat) for 6 weeks, which results in >30% increase in body weight compared to control-fed age-matched females; and offspring show elevated body weight.
At birth, a significant reduction was observed in the neuronal connectivity between the arcuate nucleus (ARC) and the paraventricular nucleus of the hypothalamus (PVN), suggesting a developmental anomaly in axon growth from ARC to PVN. Transcriptome analysis was performed on fetal ARC to determine whether anatomical changes could be accounted for by altered developmental gene expression. Significant changes were observed in the expression of two genes – DCC and Unc5d – encoding receptors for the axon growth and guidance ligand, Netrin-1. Both DCC and Unc5d were expressed by body weight regulating neurons in the ARC during gestation; and exposure of ARC neurons to Netrin-1 in vitro stimulated growth cone expansion and branching.
To identify candidate factors linking maternal obesity to altered developmental gene expression, a multiplex cytokine assay was used. This revealed significantly elevated interleukin-6 (IL6), IL17A, and interferon gamma in the fetal circulation at gestational day 17.5. Exposure of ARC neurons to IL6 in vitro abolished their ability to respond to Netrin-1.
Together these data suggest that disruption of normal Netrin-1 signaling consequent to aberrant cytokine exposure may account for altered neuronal connectivity of ARC neurons in fetuses undergoing gestation in obese dams.