Reduced melanocortin tone mediates increased feeding during pregnancy in mice

During pregnancy mammals increase their food intake to accommodate the elevated metabolic demands associated with fetal growth and development. However, the molecular and neural circuit mechanisms mediating increased feeding during pregnancy are largely unknown. Here, we demonstrate that arcuate nucleus agouti-related peptide (AgRP) neurons are activated and pro-opiomelanocortin (POMC) neurons are inhibited during pregnancy in mice. These changes are required for promoting hyperphagia during pregnancy as chemogenetic inhibition of AgRP neurons or activation of POMC neurons both reduced the feeding of pregnant mice to non-pregnant levels. Finally, we utilized single cell resolution spatial transcriptomics in the arcuate nucleus of non-pregnant and pregnant mice to characterize pregnancy-induced changes in the transcriptomic state of arcuate nucleus neurons, including significant changes in both AgRP and POMC neurons. Together, these findings outline a circuit mechanism mediating increased feeding during pregnancy, providing important mechanistic insights related to conditions at the intersection of reproduction and metabolism. HighlightsO_LIAgRP neuron activity is increased and POMC neuron activity is decreased in pregnant mice C_LIO_LIIncreased AgRP neuron activity and reduced POMC neuron activity is required for increased feeding during pregnancy C_LIO_LIPregnancy enhances responsivity of AgRP neurons to palatable food C_LIO_LIPregnancy drastically alters the transcriptional state of both AgRP and POMC neurons towards positive energy balance C_LI