Possa-Paranhos, I. C. | bioRxiv Science

bioRxiv2025

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

neuroscience↗

bioRxiv2024

Neuroanatomical dissection of the MC3R circuitry regulating energy rheostasis

Although mammals resist both acute weight loss and weight gain, the neural circuitry mediating bi-directional defense against weight change is incompletely understood. Global constitutive deletion of the melanocortin-3-receptor (MC3R) impairs the behavioral response to both anorexic and orexigenic stimuli, with MC3R knockout mice demonstrating increased weight gain following anabolic challenges and increased weight loss following anorexic challenges (i.e. impaired energy rheostasis). However, the brain regions mediating this phenotype remain incompletely understood. Here, we utilized MC3R floxed mice and viral injections of Cre-recombinase to selectively delete MC3R from medial hypothalamus (MH) in adult mice. Behavioral assays were performed on these animals to test the role of MC3R in MH in the acute response to orexigenic and anorexic challenges. Complementary chemogenetic approaches were used in MC3R-Cre mice to localize and characterize the specific medial hypothalamic brain regions mediating the role of MC3R in energy homeostasis. Finally, we performed RNAscope in situ hybridization to map changes in the mRNA expression of MC3R, POMC, and AgRP following energy rheostatic challenges. Our results demonstrate that MC3R deletion in MH increased feeding and weight gain following acute high fat diet feeding in males, and enhanced the anorexic effects of semaglutide, in a sexually dimorphic manner. Additionally, activation of DMH MC3R neurons increased energy expenditure and locomotion. Together, these results demonstrate that MC3R mediated effects on energy rheostasis result from the loss of MC3R signaling in the medial hypothalamus of adult animals and suggest an important role for DMH MC3R signaling in energy rheostasis. Key Points: O_LIMC3R signaling regulates energy rheostasis in adult mice C_LIO_LIMedial hypothalamus regulates energy rheostasis in adult mice C_LIO_LIEnergy rheostasis alters mRNA levels of AgRP and MC3R in DMH C_LIO_LIDMH MC3R neurons increase locomotion and energy expenditure C_LIO_LIMC3R expression in DMH is sexually dimorphic C_LI

neuroscience↗