Altered responses to ghrelin and food cues in AgRP neurons during pregnancy and lactation.

Pregnancy and lactation trigger many metabolic adaptations, including increased food intake to support the energy demands of the growing foetus and then to provide nutrition through milk production after birth. Ghrelin, an orexigenic hormone, activates agouti related peptide (AgRP) neurons in the arcuate nucleus to promote food intake. Here, we investigated the hypothesis that increased sensitivity to ghrelin during pregnancy and lactation may contribute to elevated maternal food intake. Acute food intake was measured after a single dose of ghrelin or vehicle across reproductive states including virgin, pregnant (Day 8 and Day 15), lactating (Day 10) mice and dams 2 weeks after weaning. In vivo GCaMP fibre photometry of the AgRP neuron population was used to measure AgRP neuronal response to ghrelin. Unlike virgin mice, pregnant mice did not show an acute increase in food intake after ghrelin injection, while ghrelin-treated lactating mice showed a greater feeding response than virgin mice. After weaning, dams showed a similar increase in food intake to that seen in virgin mice. In contrast to the loss of feeding response to ghrelin, the expected increase in growth hormone (GH) in response to ghrelin was observed in both pregnancy and lactation. Across all of the reproductive states, a significant increase in AgRP neuron activity was observed in response to exogenous ghrelin administration, although the magnitude was slightly reduced in late pregnancy. Furthermore, the ghrelin-induced increase in c-Fos expression in AgRP neurons was similar in all reproductive states, indicating that AgRP neurons remained responsive to ghrelin despite the absence of a food-intake response to ghrelin during pregnancy. Interestingly, the expected drop in AgRP neuron activity in response to the presentation of food was absent during late pregnancy and lactation. The absence of a food consumption-mediated inhibition of AgRP neuron activity suggests that an attenuated response of the AgRP neurons to feedback signals associated with eating may contribute to increases in meal duration during pregnancy and lactation. Overall, these results indicate that ghrelin resistance develops during pregnancy, suggesting that ghrelin does not contribute to elevated food intake during pregnancy. In lactation, however, enhanced ghrelin sensitivity may contribute to elevated maternal food intake. These results also indicate that adaptations to ghrelin sensitivity in pregnancy and lactation are transient as 2 weeks after weaning our results are similar to the virgin state.