Fetal origins of obesity: a novel pathway of regulating appetite neurons in the hypothalamus of growth-restricted rat offspring

PurposeFetal growth restriction causes a series of sequelae, some of which, such as hyperphagia, reduced satiety and postnatal obesity, are believed to be associated with embryonic hypothalamic neurons impairment. The mechanisms underlying the linkage of fetal brain injuries to break the energy homeostasis have not been elucidated completely. Here, we aim to investigate the effect of intrauterine energy restriction on remodeling appetite neurons in the hypothalamus of fetal and postnatal infant rats.MethodsLow-protein (8%) diet combined with 75% energy restriction was used to establish an animal model. Rats offspring brain tissues, harvested from embryo day 18 and postnatal infant day 1, were sampled for dependent regulator analyses and master neuron assessment.ResultsGrowth-restricted rats showed the increased expression of Bsx and NPY in the hypothalamus as well as remodeling hypothalamic neurons differentiation compared to controls. Intriguingly, in cells cultured in vitro test, we found that activated effects of Bsx and NPY could be exacerbated by DNMT1 inhibitor.ConclusionsIn embryonic and early postnatal stage of FGR rats, we detected high concentrations of orexigenic neurons in the hypothalamus. DNMT1 activity is correlated with early embryonic neurogenesis by mediating the expression of Bsx and NPY. It may be one of the reasons for the abnormal development of the appetite regulation pathway and higher susceptibility to obesity in FGR offspring.

Automated summary

This study aims to investigate the effect of intrauterine energy restriction on the remodeling of appetite neurons in the hypothalamus of fetal and postnatal infant rats. The results showed that growth-restricted rats had increased expression of Bsx and NPY as well as remodeling of hypothalamic neurons differentiation. In vitro experiments revealed that the activated effects of Bsx and NPY could be exacerbated by DNMT1 inhibitor. These findings suggest that high concentrations of orexigenic neurons in the hypothalamus of growth-restricted rats and DNMT1 activity may play a role in abnormal development of appetite regulation pathway and higher susceptibility to obesity in offspring.