Maternal obesity causes fetal hypothalamic insulin resistance and disrupts development of hypothalamic feeding pathways

Abstract

Objective Perinatal exposure to maternal obesity results in predisposition of offspring to develop obesity later in life. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of food intake as a cause. We aimed to define how maternal obesity impacts early development of the hypothalamus to program lasting dysfunction in feeding regulatory pathways. Methods Mice offspring of diet-induced obese mothers were compared to the offspring of lean control mothers . We analysed gene expression in the fetal hypothalamus, alongside neurosphere assays to investigate the effects of maternal obesity on neural progenitor cell proliferation in vitro . Western blotting was used to investigate the insulin signalling pathway in the fetal hypothalamus. Characterisation of cell type and neuropeptide profile in adulthood was linked with analyses of feeding behaviour. Results There was a reduction in the expression of proliferative genes in the fetal hypothalamus of offspring exposed to maternal obesity. This reduction in proliferation was maintained in vitro when hypothalamic neural progenitor cells were grown as neurospheres. Hypothalamic fetal gene expression and neurosphere growth correlated with maternal body weight and insulin levels. Foetuses of obese mothers showed hypothalamic insulin resistance, which may be causative of reduced proliferation. Furthermore, maternal obesity activated the Notch signalling pathway in neonatal offspring hypothalamus, resulting in decreased neurogenesis. Adult offspring of obese mothers displayed an altered ratio of anorexigenic and orexigenic signals in the arcuate nucleus, associated with an inability to maintain energy homeostasis when metabolically challenged. Conclusions These findings show that maternal obesity alters the molecular signature in the developing hypothalamus, which is associated with disrupted growth and development of hypothalamic precursor cells and defective feeding regulation in adulthood. This is the first report of fetal hypothalamic insulin resistance in an obese pregnancy and suggests a mechanism by which maternal obesity causes permanent changes to hypothalamic structure and function.

Maternal Metabolic Programming of the Developing Central Nervous System: Unified Pathways to Metabolic and Psychiatric Disorders

“…Recently, Dearden et al were able to demonstrate specific hypothalamic effects on the proliferative capacity of neurons. In this study, maternal overnutrition in mice resulted in decreased expression of proliferative gene markers, Bub1b, Ki67, and Pcna, coupled to reduced proliferation of neural progenitor cells (61). Furthermore, Kim and colleagues identified increased proliferation in astrocytes, suggesting overall changes in proliferative capacity in different cellular populations of the CNS (62).…”

Milk Polar Lipids Supplementation to Obese Rats During Pregnancy and Lactation Benefited Skeletal Outcomes of Male Offspring

“…[ 41 ] The neurogenesis of hypothalamus in neonates of HFD dams was reduced [ 42 ] and hypothalamic insulin resistance may contribute to the reduced proliferation of neural progenitor cells. [ 43 ] Besides, insulin signaling inactivation through PDK1 knockout in AgRP neuron downregulated hypothalamic GHRH expression, which was rescued by transactivation‐defective FoxO1. [ 14 ] In our study, maternal MFGM‐PL supplementation significantly increased the expression of hypothalamic GHRH in HFD offspring, which may be particularly relevant to the altered insulin sensitivity in hypothalamus.…”

Nutritional and developmental programming effects of insulin

“…109 A more recent study has reported that fetuses of obese dams display reduced expression of proliferative genes in the hypothalamus and disrupted neurosphere growth and that these two surrogate markers of neuronal proliferation were correlated with maternal insulin levels. 110 Insulin resistance in the developing hypothalamus, including from alterations in insulin receptor DNA promoter methylation, could explain the reduced neuroproliferative response of hypothalamic neurones to insulin in pups exposed to a maternal obesogenic environment. [110][111][112] A role for insulin in glial cell development has also been suggested.…”

“…110 Insulin resistance in the developing hypothalamus, including from alterations in insulin receptor DNA promoter methylation, could explain the reduced neuroproliferative response of hypothalamic neurones to insulin in pups exposed to a maternal obesogenic environment. [110][111][112] A role for insulin in glial cell development has also been suggested. Insulin levels during early postnatal life are positively correlated with the number of astrocytes.…”