Region-specific suppression of hypothalamic responses to insulin to adapt to elevated maternal insulin secretion during pregnancy.

4 years ago

Region-specific suppression of hypothalamic responses to insulin to adapt to elevated maternal insulin secretion during pregnancy.

Grattan, Ladyman

As part of the adaptation of maternal glucose regulation during pregnancy to ensure glucose provision to the fetus, maternal insulin concentrations become elevated. However, increased central actions of insulin, such as suppression of appetite, would be maladaptive during pregnancy. We hypothesized that central nervous system targets of insulin become less responsive during pregnancy to prevent overstimulation by the increased circulating insulin concentrations. To test this hypothesis, we have measured insulin-induced phosphorylation of Akt (pAkt) in specific hypothalamic nuclei as an index of hypothalamic insulin responsiveness. Despite higher endogenous insulin concentrations following feeding, arcuate nucleus pAkt levels were significantly lower in the pregnant group compared to the non-pregnant group. In response to an i.c.v. injection of insulin, insulin-induced pAkt was significantly reduced in the arcuate nucleus and ventromedial nucleus of pregnant rats compared to non-pregnant rats. Similar levels of insulin receptor beta and PTEN, a negative regulator of the PI3K/Akt pathway, were detected in hypothalamic areas of non-pregnant and pregnant rats. In the ventromedial nucleus however, levels of phosphorylated PTEN were significantly lower in pregnancy, suggesting that reduced inactivation of PTEN may contribute to the attenuated insulin signaling in this area during pregnancy. In conclusion, these results demonstrate region-specific changes in responsiveness to insulin in the hypothalamus during pregnancy and this may represent an adaptive response to minimize the impact of elevated circulating insulin on the maternal brain.

Publisher URL: http://doi.org/10.1210/en.2017-00600

DOI: 10.1210/en.2017-00600